(9781585286010 - Basic Concepts in Medicinal Chemistry) Answers To Chapter Questions

APP
ANSWERS TO
CHAPTER QUESTIONS
CHAPTER 2
STRUCTURE ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
1. Answers provided in table below.
Functional Group Name Contribution to Water and/or Lipid Solubility

A Halogen (chlorine atom) Lipid Solubility
B Alicyclic ring, alkyl ring, cycloalkane Lipid Solubility
C Tertiary amine (piperazine) Water Solubility
D Heterocyclic ring system (pyrrolopyridine) Hydrocarbons: Lipid Solubility
Nitrogen atoms: Water Solubility
E Aromatic ring; phenyl ring; aromatic hydrocarbon Lipid Solubility
F Sulfonamide Water Solubility
G Secondary aromatic amine/aniline Water Solubility
H Ether Hydrocarbons: Lipid Solubility
Oxygen atom: Water Solubility
2. The sulfonamide and tertiary amine will be primarily ionized in most physiological
environments and can participate in ion-dipole interactions (as the ion) with water.
In the event that they are unionized, they could participate in hydrogen bonding
interactions with water. The nitrogen atoms of the heterocyclic ring system, as
well as the secondary aromatic amine, and the oxygen atom of the ether will not
be appreciably ionized, but can participate in hydrogen bonding interactions
with water. Thus, all of these functional groups contribute to the water solubility
of venetoclax. The halogen as well as the hydrocarbon chains and rings are not
able to ionize or form hydrogen bonds with water and thus contribute to the lipid
solubility of venetoclax.
477
Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

478 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Answers provided in table below.
Electron Donating or Withdrawing Resonance or Induction

A Electron Withdrawing Induction
B Both Donates electrons into the aromatic ring through resonance.
Withdraws electrons from adjacent methylene groups
through induction.
C Electron Donating Resonance
D Electron Withdrawing Induction (from aromatic ring)
Resonance (from ionized sulfonamide)
E Electron Withdrawing Resonance
Checkpoint Drug 2: Elamipretide
1. Answers provided in the grid below.
Character: Function:
Name of Functional Group Hydrophobic, Hydrophilic, or both Contribute to Solubility or Absorption
A Guanidine Hydrophobic (R) Absorption (R)
Hydrophilic (H2NCNHNH) Solubility (H2NCNHNH)
B Primary amine Hydrophobic (R) Absorption (R)
Hydrophilic (NH2) Solubility (NH2)
C Amide Hydrophobic (R) Absorption (R)
Hydrophilic (C=ONH2) Solubility (C=ONH2)
D Aromatic hydrocarbon; Hydrophobic (R) Absorption (R)
aromatic ring; phenyl ring
E Phenol Hydrophobic (R) Absorption (R)

Hydrophilic (OH) Solubility (OH)
R = carbon scaffolding
2. Part A: Every amino acid has an amine (basic), a unique side chain, and a
carboxylic acid (acidic). As building blocks of proteins, the amine and carboxylic
acid of adjacent amino acids are linked to form an amide or peptide linkage
(neutral).
Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the

amine and carboxylic acid of adjacent amino acids are linked to form a peptide
bond (amide = neutral). The easiest way to read these kinds of molecules is to look
for the pattern “amine-side chain-carbonyl” (representing one amino acid) and to
completely ignore the fact that the amine and adjacent carboxylic acid are really
an amide. In the diagram below, the “amine-side chain-carbonyl” pattern for the
first two amino acids/amino acid derivatives is shown.

APPENDIX: ANSWERS TO CHAPTER QUESTIONS 479
Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the amine and
H2N NH
NH2
N
H
carbonyl side chain
amine O O
H H
N N
H2N N NH 2
H
side chain O amine O
carbonyl
H 3C
C H3
OH
Using this pattern, the first amino acid in the sequence is the amino acid arginine,
the second amino acid is a derivative of tyrosine, the third amino acid is lysine, and
the fourth amino acid is phenylalanine.
Part
C:Part
TheC:portions of the
The portions ofmolecule thatthat
the molecule represent arginine,
represent arginine,lysine,
lysine,and
andphenylalanine have
phenylalanine have been boxed.
arginine
lysine
phenylalanine
Part D: The second amino acid is a derivative of tyrosine.
REVIEW QUESTIONS
3. Part A: Functional groups are identified in the structure shown below.
amidine
thioether
guanidine H
N | Downloaded 07/13/21 09:53 AM UTC
Unauthenticated
NH 2 N S H
Amino Acid Side Chain Amino Acid Side

Evaluation: Amino Acid Side Chain Chain Evaluation:
Name of Amino Acid or Hydrophobic, Hydrophilic, Evaluation: Nucleophilic,
Amino Acid Derivative or Both Acidic, Basic, Neutral Electrophilic, NA
1 Arginine Hydrophilic (NHC=NHNH2) Basic NA
Hydrophobic (R)
2 Tyrosine derivative Hydrophilic (OH) Acidic Nucleophilic
Hydrophobic (R)
3 Lysine Hydrophilic (NH2) Basic Nucleophilic
Hydrophobic (R)
4 Phenylalanine Hydrophobic Neutral NA
R = carbon scaffolding.
REVIEW QUESTIONS
Box Functional Group Name

A Guanidine
B Secondary amine
C Cycloalkane (cyclopropane)
D Carboxylic acid
E Amide
F Sulfonamide
G Aromatic hydrocarbon (or aromatic ring)
Box Functional Group Name

A Ketone
B Cycloalkene (cyclohexadiene)
C Secondary alcohol
D Aliphatic halogen
E Ester
F Cycloalkane

REVIEW QUESTIONS
amidine
thioether
guanidine H
N
NH 2 N S H
N
H2 N N S SO2 NH2
aromatic heterocycle
(1.3 thiazole)
Part B: The aromatic heterocycle (1,3 thiazole) and the sulfonamide are both
electron withdrawing groups and will significantly decrease the magnitude of the
pKa values for both the guanidine and amidine. The experimentally measured pKa
values for the guanidine and the amidine are in the range of 6.7–6.9.
Part C: The amidine is not protonated at physiological pH because the

sulfonamide is an electron withdrawing group and will pull (or withdraw) electrons
from the amidine through induction. This will decrease the ability of the amidine to
attract protons (H+); therefore, its basicity will decrease.
The experimentally measured pKa values for famotidine are all in the range of
6.7 and 6.9. The amidine, guanidine, and aromatic heterocycle are all basic in
character. At pH = 7.4, the pH > pKa for these functional groups and, therefore,
the basic functional groups are predominantly unionized in this pH environment.
4. Part A: Answers provided in the grid below.
Contribution to Water
Name of Three Oxygen Hydrophilic Solubility
Containing Functional and/or and/or Hydrogen Bond Acceptor,
Groups Hydrophobic Lipid Solubility Donor, Both, or Neither
Primary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor
Hydrophobic (R) Lipid solubility (R) and donor
Secondary alcohol Hydrophilic (OH) Water solubility (OH) Hydrogen bond acceptor
Hydrophobic (R) Lipid solubility (R) and donor
Ether Hydrophilic (O) Water solubility (O) Hydrogen bond acceptor

Hydrophobic (R) Lipid solubility (R)
Part B: The primary and secondary alcohols, as well as the ethers, all have
hydrophilic character. The alcohols (primary and secondary) are able to interact
with water as both hydrogen bond acceptor and donors, which means that they
make a sizable contribution to the water solubility of lactulose. The ethers are able
to interact with water as a hydrogen bond acceptor only and, therefore, make
somewhat less of a contribution to water solubility as compared to the alcohols.

+2
2
482 BASIC CONCEPTS IN MEDICINAL CHEMISTRY +2
+2
2+
Part C: The primary and secondary alcohols, 2
+ 2 as2well as the ethers all have
hydrophilic character. The alcohols (primary 2 and
+
secondary) are able to interact
with water as both hydrogen bond acceptors and donors, which means that they
will be able to attract and interact with water. The2ethers
+ are able to interact with
water as a hydrogen bond acceptor only and, therefore,
2+ make somewhat less of a
contribution to the drug’s ability to attract and interact with water.
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5. Part A: Answers provided in the grid below.

Contribution to Water Solubility and/or
Name of Functional Group Hydrophilic and/or Hydrophobic Lipid Solubility
Aromatic hydrocarbon Hydrophobic Lipid solubility
alkane (branched)
Aliphatic Hydrophobic Lipid solubility
Tertiary amine Hydrophobic (R) Lipid solubility (R)
Hydrophilic (N atom) Water solubility (N atom)
3DJHRI
Part B: Butenafine has several functional groups (aromatic hydrocarbons, branched

aliphatic alkane) that are hydrophobic in character and contribute significantly to
lipid solubility and drug absorption. These features contribute to the ability of the
drug to easily absorb into the skin, which has considerable lipid character.

Replacement Structures for Appendix Proof Pages (Pages 1-47)
Page 7, answer to question 6 (One of the circles is not “crisp”; looks like someone drew a pencil around
it) APPENDIX: ANSWERS TO CHAPTER QUESTIONS 483
6. Functional groups that influence the shape of each molecule have been circled.
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Amlodipine Clonidine Oxymetazoline
7. Functional group and explanation provided below.

Page 17: Under Part B (there were errors in the captions)
&KDQJHLQVWHULFIDFWRU
2+ + 2+ +
Sulfonamide
+2 1 pKa = 4.3
1 & +
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O & +
pKa = 8.0 O & +
H
+2 N S +2 N
H
N N O
(SLQHSKULQH O NO $OEXWHURO
O

N
8. The only structural difference betweennitrogen
these two molecules is the presence of a
Heterocyclic
N
H parent drugpKand
tertiary amine in the a = 3.5
an N-methylated secondary amine in the
7KHDGGLWLRQRIRQHIXQFWLRQDOJURXSFDQ
active metabolite. The parent drug (with the tertiary amine) selectively inhibits the
reuptake of serotonin. The active metabolite (desmethyl metabolite) selectively
inhibits the reuptake of norepinephrine. This change in the number of methyl
substituents represents6a change in the steric character of the molecule. 6
9. Part A: The portion of the

1 molecule designated as “A” is the amino acid valine.1 &O
The side chain of this amino acid is hydrophobic in character and will improve the
ability of the drug to be absorbed across lipophilic membranes. This characteristic
will decrease the water solubility of the drug.
&+ & +
3URPD]LQH 1 1
Part B: The portions of the molecule designated as “B” and “C” resemble the
&KORUSURPD]LQH
& +
side chain of the amino acid phenylalanine. The side chain of this amino acid is & +

hydrophobic in character and will interact with hydrophobic regions present within
the biological target. The most likely interactions would be with the side chains
of the aromatic amino acids phenylalanine, tyrosine, or tryptophan; however, it
could also interact with the side chains of the aliphatic amino acids, alanine, valine,
leucine, or isoleucine. The ritonavir side chains “B” and “C” can also participate
in π-π stacking interactions with the side chains of phenylalanine, tyrosine,
tryptophan, and histidine present within the biological target. It is also possible
for these side chains to participate in cation-π interactions with lysine and arginine
that are ionized at physiological pH.

CHAPTER 3
CHAPTER 3
1. Acidic and basic functional groups along with normal pKa ranges are shown below.
1. Acidic and basic functional groups along with normal pKa ranges are shown below.
Sulfonamide (Acidic)
Normal pKa range: 4.5-11
Aromatic amine (Basic) Aromatic amine (Basic)

Normal pKa range: 2-5 Normal pKa range: 2-5
Cl
O O
H
N S N
H
N N O
O NO2
O
Venetoclax
N
Tertiary amine (Basic) N
Normal pKa range: 9-11 H Heterocyclic nitrogen (Basic)
Normal pKa range: 1-5
2. Venetoclax is an amphoteric drug because its structure contains both acidic and
basic functional groups.
5. The ionized
3. There form
are twoof the factors
main tertiarythat
amine is showntobelow.
contribute the enhanced acidity of the
sulfonamide functional group. First, this functional group is directly attached to
a carbonyl group. Similar to sulfonylureas, this adjacent carbonyl enhances the
acidity of the sulfonamide through resonance stabilization of the negative charge.
Once the proton leaves, the resulting negative charge can be equally delocalized
to all three adjacent oxygen atoms. Second, the nitro group on the adjacent
aromatic ring can withdraw electrons from the aromatic ring through resonance.
This decreases the electron density of the aromatic ring and causes an inductive
effect that withdraws electrons from the adjacent sulfonamide. The overall effect
of this nitro group is somewhat decreased due to the ability of the aromatic
amine to donate electrons through resonance into this same aromatic ring. Since
Venetoclax
the electron withdrawing properties of the nitro group are stronger than the
electron donating properties of the aromatic amine, the net result is an electron
withdrawing effect that enhances the acidity of the sulfonamide group.
4. Five-membered rings that contain a single nitrogen atom are not basic because
the lone pair of electrons on the nitrogen atom is involved in the aromaticity or
resonance delocalization of the ring and unavailable for binding to a proton. The
presence of a second nitrogen atom within the five-membered ring enhances
basicity as discussed in the chapter; however, in this case, the second nitrogen

Tertiary amine (Basic) N
Normal pKa range: 9-11 H Heterocyclic nitrogen (Basic)
Normal
APPENDIX: ANSWERS TOpKa range:
CHAPTER 1-5
QUESTIONS 485
atom is in the six-membered pyridine ring. This nitrogen atom is basic because the
lone pair of electrons on the nitrogen atom is oriented perpendicular to the plane
of the aromatic π electrons. Thus, the lone pair of electrons are involved in the
5. The ionized form ofofthe
aromaticity thetertiary
ring andamine is shown
are available to below.
bind to a proton.
5. The ionized form of the tertiary amine is shown below.
Venetoclax
Character: pKa Value or Range

Name of Functional Group Acidic, Basic, Neutral (NA is acceptable)
A Guanidine Basic 12.5*
B Primary amine Basic 9–11
C Amide Neutral NA
D Phenol Acidic 9–10

*
The pKa range for guanidine can dip as low as 6, especially if the functional group is attached to one or more electron
withdrawing groups, as found in the H2 antagonist class of drugs.
2. Functional group C is an amide. The carbonyl carbon is electron poor due to

the electronegativity of the adjacent oxygen atom and the resulting dipole.
This carbon atom looks to its neighbor nitrogen atom for electron density. The
neighboring nitrogen atom has a non-bonding pair of electrons that is available
(via resonance) to donate electron density to the electron deficient carbon atom.
Because this non-bonding pair of electrons is busy helping the neighbor electron
deficient carbon atom, it is unavailable to participate as a proton acceptor (base).
By way of reminder, the electronegative oxygen atom has two pairs of non-
bonding electrons, but these electrons are held too tightly to the nucleus of the
oxygen atom to participate as a proton acceptor (base). As a result, amides are
neutral in character.

3. The ionization states and acid/base character are provided below.
Stomach (pH=1) Acid/Base Intestine (pH=8) Acid/Base Urine (pH=5) Acid/Base

Ionized, Character at Ionized, Character at Ionized, Character at
Unionized, NA pH=1 Unionized, NA pH=8 Unionized, NA pH=5
A Ionized Acidic Ionized Acidic Ionized Acidic
B Ionized Acidic Ionized Acidic Ionized Acidic
C NA Neutral NA Neutral NA Neutral
D Unionized Acidic Unionized Acidic Unionized Acidic
Functional group A (guanidine) is basic in character with a pKa = ~12.5. It will be

ionized in all three physiological locations because the environmental pH<pKa of
the functional group. In its ionized form, a guanidine is a proton donor (acidic).
Functional group B (primary amine) is basic in character with a pKa range = 9–11.
It will be ionized in all three physiological locations because the environmental
pH<pKa of the functional group. In its ionized form, a primary amine is a proton
donor (acidic).
Functional group C (amide) is neutral in character. It is not an ionizable functional
group, so NA should be placed in the grid.
Functional group D (phenol) is acidic in character with a pKa = 9–10. It will be
unionized in all three physiological locations because the environmental pH<pKa of
the functional group. In its unionized form, a phenol is a proton donor (acidic).
4. The guanidine of arginine, the primary amine of lysine, and the phenol of the
Checkpoint Drugderivative
tyrosine 2: Elamipretide
are all ionizable. Don’t forget that this peptide-based drug has
an amino- and a carboxy terminus!!! In this case, the carboxy terminus carboxylic
4. The guanidine
acid hasofbeen
arginine,
maskedtheasprimary amine
an amide, of lysine,
but the and the phenol
amino terminus primary of the istyrosine
amine still
present and is ionizable.

REVIEW QUESTIONS
REVIEW QUESTIONS
1. Acidic and basic functional groups are identified below.
Efegatran
Nelfinavir
Losartan
Sulfamethazine
CH3
N
H CH3
HO
O
Isalmadol
OH O
Drug Name Acidic Functional Groups Basic Functional Groups

Efegatran Carboxylic acid Secondary amine
Guanidine
Nelfinavir Phenol Tertiary amine
(piperidine)
Sulfamethazine Sulfonamide Aniline
Losartan Tetrazole Imidazole
Isalmadol Phenol Tertiary amine

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2. Acidic functional groups have been modified to show the ionized form.
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3. Basic functional groups have been modified to show the ionized form.
+&
1+ + +
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2 1 +
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1HOILQDYLU

4. Functional groups that are acidic when they are in their ionized form are identified
below.
Efegatran Sulfamethazine Nelfinavir Losartan Isalmadol

Secondary amine Aniline Tertiary amine Imidazole Tertiary amine
(piperidine)
Guanidine
Functional groups that are basic when they are in their ionized form are identified
below.
Efegatran Sulfamethazine Nelfinavir Losartan Isalmadol

Carboxylic acid Sulfonamide Phenol Tetrazole Phenol
5. Amphoteric: contains at least one acidic and at least one basic functional group.
All of the drugs in Question #1 are amphoteric in nature.
Acidic, Basic, or
Drug Name of Functional Group(s) Approximate pKa Value(s) Amphoteric
Bromocriptine Heterocycle (tertiary amine) pKa = 9–11 Basic
Imipenem Carboxylic acid pKa = 2.5–5 Amphoteric
Amidine pKa = 10–11
Physostigmine Heterocycle (tertiary amine) pKa = 9–11 Basic
Aniline pKa = 2–5
7. Part A: Colesevelam contains a neutral quaternary ammonium salt as a component

of the polymer. It also contains ionizable functional groups (primary amine,
secondary amine) both of which are basic in character. Evaluating the entire
polymeric structure, colesevelam is considered basic in character. Because
colesevelam will dissociate into ions in solution, it is therefore classified as an
electrolyte.
Part B: Drugs that contain one or more functional groups that are anionic
(negatively charged) when in an environment of pH ~8 will exchange for the
chloride ion in the polymer. The drug will then be associated with the polymer and
be eliminated via a fecal route. This results in less drug available to be absorbed
into the body (also less bile acids being removed). This will likely reduce the
therapeutic effectiveness of the drug because a portion of the dose was removed
by the polymer.
Part C: Repaglinide (carboxylic acid), gliclazide (sulfonylurea), ciprofloxacin

(carboxylic acid), and irbesartan (tetrazole) are all likely to be anionic at pH ~8 and
therefore will be sequestered by the polymeric drug.

8. Part A: Ionizable functional groups are listed in the table below.
Acidic Functional Groups Basic Functional Groups

Repaglinide Carboxylic acid Aniline
Gliclazide Sulfonylurea Heterocycle (tertiary amine)
Ciprofloxacin Carboxylic acid Aniline
Heterocycle (tertiary amine)
Irbesartan Tetrazole Imine
Part B: The acidic and/or basic character of each drug molecule is provided below.
Acidic Character, Basic Character, or Both Acidic and Basic Character

Repaglinide Acidic and Basic Character
Gliclazide Acidic and Basic Character
Ciprofloxacin Acidic and Basic Character
Irbesartan Acidic and Basic Character

9. The acidic, (DFKRIWKHGUXJPROHFXOHVEHORZFRQWDLQVDWOHDVWRQHLRQL]DEOHIXQFWLRQDOJUR

basic, or amphoteric character of the four drugs is provided below.
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CHAPTER 4
1. Part A:The two aromatic amines are weakly basic due to the presence of other
electron withdrawing groups attached to their respective phenyl rings. As
discussed in Chapter 3, aromatic amines are much less basic than aliphatic or
alicyclic amines due to their ability to donate electrons into the aromatic ring
CHAPTER through4resonance. This donating ability can be either enhanced or hindered
due to the presence of other functional groups. For aromatic amine 1, the para
carbonyl
STRUCTURE ANALYSIS on the aromatic ring is electron withdrawing, mostly through inductive
CHECKPOINT
effects, and enhances the flow of electrons away from the nitrogen and further
decreases
Checkpoint its basicity.
Drug Additionally, the meta ether oxygen atom may play a role.
1: Venetoclax
While both the aromatic amine and the ether oxygen can donate electrons into the
aromatic ring, the oxygen atom is more electronegative than the nitrogen atom
and thus withdraws electrons from the nitrogen atom via induction. Both of these
1. Parteffects
A: Thedecrease
two aromatic amines are
the availability weakly
of the basic
lone pair of due to the
electrons presence
and thus theof other electron
basicity
of aromatic amine 1.
Weakly basic
2
1
Venetoclax
For aromatic amine 2, the ortho nitro group is electron withdrawing in character and will
greatly decrease the basicity of the amine through resonance delocalization as shown below.
..

Replacement Structures for Appendix Proof Pages (Pages 1-47)
Page 7, answer to question 6 (One of the circles
APPENDIX: is notTO
ANSWERS “crisp”;
CHAPTERlooks like someone
QUESTIONS 493 drew a penc
it)
aromatic amine 2, the ortho nitro group is electron withdrawing in character and will
For aromatic amine 2, the ortho nitro group is electron withdrawing in
atly decrease the basicity
character andof the
will amine
greatly through
decrease the resonance delocalization
basicity of the amine throughas shown below.
resonance
delocalization as shown below.
..
Part B: The normal pKa range for a tertiary amine is 9–11. Given this piece of
information, the pKa of 8.0 should be assigned to this basic functional group. The
Amlodipine
lower basicity may be due to steric hindrance or adjacentClonidine
functional groups. This
leaves the heterocyclic nitrogen atom (basic) and the sulfonamide (acidic) and the
pKa values of 3.5 and 4.3. The normal pKa range for a sulfonamide is 4.5–11, and
the normal pKa range for heterocyclic nitrogen atoms is 1–5. While both of these
pKa values fall with the normal range for heterocyclic nitrogen atoms, the pKa value
of 3.5 belongs to the heterocyclic nitrogen atom. This is because the pKa value
of
Page4.317:
is only
Underslightly lower
Part B than
(there theerrors
were normalinrange for sulfonamides, while the pKa
the captions)
value of 3.5 is too far outside this range. A full explanation of the pKa value for the
sulfonamide can be found in the answers for Chapter 3.
Sulfonamide
pKa = 4.3
Cl Tertiary amine
pKa = 8.0 O O
H
N S N
H
N N O
O NO
O
N
Heterocyclic nitrogen
N pKa = 3.5
H

2. Part A: The tertiary amine and the heterocyclic nitrogen will be primarily ionized,
and the sulfonamide will be primarily unionized.
Part B: The tertiary amine and the sulfonamide will be primarily ionized, and the
heterocyclic nitrogen will be primarily unionized.
Part C: The tertiary amine and the sulfonamide will be primarily ionized, and the
heterocyclic nitrogen will be primarily unionized.
3. Part A: To use the Rule of Nines, the difference between the pH and the pKa must
be an integer (i.e., 1, 2, 3). In evaluating the above nine scenarios, there is only
one scenario that meets this criteria, the sulfonamide at a urine pH of 5.3. For
this sulfonamide, the absolute value between the pH and the pKa is equal to 1;
thus, there is a 90:10 ratio. Because the sulfonamide (pKa = 4.3) is acidic, it will be
primarily ionized in a basic environment (pH = 5.3). We can then use this ratio to
determine that it will be 90% ionized.
Part B: There are two methods that allow the Rule of Nines to approximate the
percent to which a functional group is ionized even if the difference between the
pH and the pKa is not an integer. The first method is to round either the pH of
the environment or the pKa of the functional group so that there is an integral
difference. Using the tertiary amine, absolute value between the pH and the pKa
is approximately equal to 6; thus, there is an approximate ratio of 99.9999:0.0001.
Because the tertiary amine (pKa = 8.0) is basic, it will be primarily ionized in an
acidic environment (pH = 1.8). We can then use this ratio to determine that it
will be approximately 99.9999% ionized. The second method is to establish a
range. Using sulfonamide, the absolute value between the pH and the pKa is 2.5.
Since the sulfonamide (pKa = 4.3) is acidic, it will be primarily unionized in an
acidic environment (pH = 1.8). If the absolute value was 2, then 99% would be
unionized, and if the absolute value was 3, then 99.9% would be unionized. Since
the absolute value lies between 2 and 3, then we can conclude that the percent to
which the sulfonamide is unionized is somewhere between 99% and 99.9%.

Heterocylic nitrogen
pKa = 3.5
4. Part A: As determined in question 1B, the pK of 4.3 belongs to the acidic

A: As determined in question
sulfonamide 1B, thegroup,
functional pKa ofthus
4.3 the
belongs to
ionized
a
the acidic
form sulfonamide
is the Base Form andfunctional
the
unionized form is the Acid Form.
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ሾ ሿ
ሾ ሿ
͵Ǥͳ ൌ ͶǤ͵ ൅
ሾ ሿ
ሾ ሿ
െͳǤʹ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲ͸͵ ሾ ሿ

ͲǤͲ͸͵ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This ratio indicates that for every one molecule that contains the functional group
This ratio
in theindicates that for every
acid (or unionized) one
form, molecule
there that
is 0.063 containsthat
molecule thecontains
functional
thegroup in
functional
the group in the base (or ionized) form. The following equations can then be used
to correctly calculate the percentage of the molecules that are ionized and the
percentage that are unionized.
ͲǤͲ͸͵
0.063 molecule in base form ൅ ͳǤͲ
+ 1.0 molecule in acid form –ൌ1.063
ͳǤͲ͸͵
total molecules
ൌ ൌ
ͳ
ൌ ൈ ͳͲͲΨ ൌ ͻͶǤͳΨ
ͳǤͲ͸͵
ͲǤͲ͸͵

0.063 Molecule in Unionized Form
ൌ ൈ ͳͲͲΨ ൌ ͷǤͻΨ
ͳǤͲ͸͵
Part B: As determined in question 1B, the pKa of 8.0 belongs to the basic tertiary amine
The question asks for the percent that will be ionized, so the correct answer is
5.9%.
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െͲǤ͹ ൌ
ͲǤͲ͸͵
496 BASIC CONCEPTS IN MEDICINAL ͳǤͲ͸͵
CHEMISTRY
Part B: As determined in question 1B, the pKa of 8.0 belongs to the basic tertiary
Part B: As determined in question
amine functional 1B,thus
group, thethe
pKionized
a of 8.0 form
belongs
is thetoAcid
the Form
basicand
tertiary amine
the unionized
form is the Base Form.
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ሾ ሿ
͹Ǥ͵ ൌ ͺǤͲ ൅
ሾ ሿ
ሾ ሿ
െͲǤ͹ ൌ
ሾ ሿ
ሾ ሿ ͲǤʹͲ ሾ ሿ

ͲǤʹͲ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
in the acid (or ionized) form, there is 0.20 molecule that contains the functional
group in the base (or unionized) form. The following equations can then be used
This ratio indicates that for every one molecule that contains the functional group in the
ͲǤʹͲ
0.20 molecule in base form൅+ͳǤͲ
1.0 molecule in acid form –ൌ1.20
ͳǤʹͲ
total molecules
ൌ ൌ
ͲǤʹͲ
ൌ ൈ ͳͲͲΨ ൌ ͳ͸Ǥ͹Ψ
ͳǤʹͲ

ͳǤͲ
ൌ ൈ ͳͲͲΨ ൌ ͺ͵Ǥ͵Ψ
ͳǤʹ
The question asks for the percent that will be ionized, so the correct answer is 83.3%.
83.3%.
Part C: As determined in Question 1B, the pKa of 3.5 belongs to the basic heterocyclic
nitrogen
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ͳǤͲ
ൌ ൈ ͳͲͲΨ ൌ ͺ͵Ǥ͵Ψ
ͳǤʹ
The question
Part C:asks for the percent
As determined that will
in Question 1B,bethe
ionized, so the
pK of 3.5 correct
belongs answer
to the basic is 83.3%.
a
heterocyclic nitrogen atom, thus the ionized form is the Acid Form and the
unionized form is the Base Form. The functional group is 30% ionized. This
Part C: As determined in Question
means that 1B, molecules
for every 100 the pKa ofof3.5 belongs to
venetoclax, 30 the basicwill
of them heterocyclic
have an ionized
heterocyclic nitrogen atom, and 70 will have an unionized heterocyclic nitrogen
nitrogen atom. Thus, the [Base Form]/[Acid Form] ratio is 70:30. Using this ratio and the
given pKa, the pH can be determined.
ሾ ሿ
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ሾ ሿ
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ൌ ͵Ǥͷ ൅
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ൌ ͵Ǥͷ ൅ ʹǤ͵

ൌ ͵Ǥͷ ൅ ͲǤ͵͸
ൌ ͵Ǥͺ͸

1. Answer provided in table below.
Character:
Name of Functional Group Acidic, Basic, Neutral pKa Value or Range
A Guanidine (arginine side chain) Basic ~12.5
B Primary amine (lysine side chain) Basic ~10.5
C Phenol (modified tyrosine side chain) Acidic ~10.5
D Primary amine (peptide backbone) Basic ~10.5
2. To determine the extent to which a functional group is ionized in a given

physiological environment (qualitatively or quantitatively), you must know several
facts and must select how to set the problem up. You will need to know the pKa of
the functional group and the pH of the environment (facts) and then, in order to
set the problem up, you must know whether the functional group is acidic or basic.
For example, using the Henderson-Hasselbalch equation to solve the problem

qualitatively, you must be able to identify the base form (ionized form for acids;
unionized form for bases) and the acid form (unionized form for acids; ionized form
for bases) of the drug molecule. When using qualitative methods, remember that
when pH < pKa (for acids), the functional group is predominantly unionized; but,
when pH < pKa (for bases), the functional group is predominantly ionized.

3. Answers provided in the tables below.
Character: Primarily Ionized (>50%)

Acidic, Basic, pKa Value or Primarily Unionized (<50%)
Name of Functional Group Neutral Range pH = 2
A Guanidine (arginine side chain) Basic ~12.5 Primarily ionized
B Primary amine (lysine side chain) Basic ~10.5 Primarily ionized
C Phenol (modified tyrosine side chain) Acidic ~10.5 Primarily unionized
D Primary amine (amino terminus) Basic ~10.5 Primarily ionized

Name of Functional Group Neutral Range pH=5

Name of Functional Group Neutral Range pH=7.4
Functional group A (guanidine) is basic in character with a pKa =~12.5. It will be

primarily ionized in all three physiological locations because the environmental
pH<pKa of the functional group. In its ionized form, a guanidine is a proton donor
(acidic).
Functional group B (primary amine) is basic in character with a pKa =~10.5. It will
be primarily ionized in all three physiological locations because the environmental
pH<pKa of the functional group. In its ionized form, a primary amine is a proton
donor (acidic).
Functional group C (phenol) is acidic in character with a pKa =~10.5. It will be

primarily unionized in all three physiological locations because the environmental
pH<pKa of the functional group. In its ionized form, a phenol is a proton acceptor
(basic).
Functional Group D (amino terminus primary amine) is basic in character with a

pKa =~10.5. It will be primarily ionized in all three physiological locations because
the environmental pH<pKa of the functional group. In its ionized form, a primary
amine is a proton donor (acidic).

4. Answers provided in the tables below.
Character:
Acidic, Basic, pKa Value or Percent Ionized
A Guanidine (arginine side chain) Basic ~12.5 99.9999921%
B Primary amine (lysine side chain) Basic ~10.5 99.99921%
C Phenol (modified tyrosine side chain) Acidic ~10.5 0.00079%
D Primary amine (amino terminus) Basic ~10.5 99.99921%
Character:
Acidic, Basic, pKa Value or Percent Ionized
A Guanidine (arginine side chain) Basic ~12.5 99.99%
B Primary amine (lysine side chain) Basic ~10.5 99.01%
C Phenol (modified tyrosine side chain) Acidic ~10.5 0.99%
Part A: pH = 5.4
D Primary amine (amino terminus) Basic ~10.5 99.01%
For thePart A: pH =functional

guanidine 5.4 group at pH=5.4:
For the guanidine functional group at pH=5.4:
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ሾ ሿ
ͷǤͶ ൌ ͳʹǤͷ ൅
ሾ ሿ
ሾ ሿ
െ͹Ǥͳ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͲͲͲͲͲͲ͹ͻ ሾ ሿ

ͲǤͲͲͲͲͲͲͲ͹ͻ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This ratio
This ratio indicates
indicates that
that for for every
every one molecule
one molecule thatthat contains
contains thethe functionalgroup
functional groupin
in the acid (or ionized) form, there is 0.000000079 molecule that contains the
the functional group in the base (or unionized) form. The following equations can then
be used to correctly calculate the percentage of the molecules that are ionized
and the percentage that are unionized.
ͲǤͲͲͲͲͲͲͲ͹ͻ ൅ ͳǤͲ
ൌ ͳǤͲͲͲͲͲͲͲ͹ͻ
ൌ ൌ

the
ͲǤͲͲͲͲͲͲͲ͹ͻ ൅ ͳǤͲ
0.000000079ൌmolecule in base form + 1.0 molecule in acid form
ͳǤͲͲͲͲͲͲͲ͹ͻ
= 1.000000079 total molecules
ൌ ൌ
ͲǤͲͲͲͲͲͲͲ͹ͻ
ൌ ൈ ͳͲͲΨ
ൌ ͲǤͲͲͲͲͲ͹ͻΨ
ͳǤͲ

The question asks for the percent
ൌ that will be ionized, so the correct
ൈ ͳͲͲΨ answer is
ൌ ͻͻǤͻͻͻͻͻʹͳΨ
ͻͻǤͻͻͻͻͻʹͳΨ.
99.9999921%.
For both primary amine functional groups at pH=5.4:
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ሾ ሿ
ͷǤͶ ൌ ͳͲǤͷ ൅
ሾ ሿ
ሾ ሿ
െͷǤͳ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͲͲͲͲ͹ͻ ሾ ሿ

ͲǤͲͲͲͲͲ͹ͻ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This ratio indicates that for every one molecule that contains the functional
This ratio indicates that for every one molecule that contains the functional group in
group in the acid (or ionized) form, there is 0.0000079 molecule that contains the
the functional group in the base (or unionized) form. The following equations can then
be used to correctly calculate the percentage of the molecules that are ionized
and the percentage that are unionized.
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ͳǤͲͲͲͲͲ͹ͻ
the
0.0000079 molecule in base form + 1.0 molecule in acid form
ൌ ൌ
ͲǤͲͲͲͲͲ͹ͻ
ൌ ൈ ͳͲͲΨ ൌ ͲǤͲͲͲ͹ͻΨ
ͳǤͲͲͲͲͲ͹ͻ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͻͻͻʹͳΨ
ͳǤͲͲͲͲͲ͹ͻ
The 99.99921%.
question asks for the percent that will be ionized, so the correct answer is
ͻͻǤͻͻͻʹͳΨ.
For the phenol functional group at pH=5.4:
ሾ ሿ

ሾ ሿ
ሾ ሿ
ͷǤͶ ൌ ͳͲǤͷ ൅
ሾ ሿ
ሾ ሿ
െͷǤͳ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͲͲͲͲ͹ͻ ሾ ሿ

ͲǤͲͲͲͲͲ͹ͻ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
in the acid (or unionized) form, there is 0.0000079 molecule that contains the
the functional group in the base (or ionized) form. The following equations can then be
used to correctly calculate the percentage of the molecules that are ionized and
the percentage that are unionized.
ൌ ൌ
ͲǤͲͲͲͲͲ͹ͻ
ͳǤͲͲͲͲͲ͹ͻ
the
0.0000079 molecule in base form + 1.0 molecule in acid form
ൌ ൌ
ͲǤͲͲͲͲͲ͹ͻ
ͳǤͲͲͲͲͲ͹ͻ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͻͻͻʹͳΨ
ͳǤͲͲͲͲͲ͹ͻ
The question
0.00079%.asks for the percent that will be ionized, so the correct answer is
ͲǤͲͲͲ͹ͻΨ.
Part B: pH = 8.5
For the guanidine functional group at pH=8.5
For the guanidine functional group at pH=8.5
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
Part B: pH = 8.5
ሾ ሿ
ͺǤͷ ൌ ͳʹǤͷ ൅
ሾ ሿ
ሾ ሿ
െͶ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͲͲͳ ሾ ሿ

ͲǤͲͲͲͳ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
the group in the base (or unionized) form. The following equations can then be used
ͲǤͲͲͲͳ ൅ ͳǤͲ ൌ ͳǤͲͲͲͳ
ൌ ൌ
ͲǤͲͲͲͳ
ൌ ൈ ͳͲͲΨ ൌ ͲǤͲͲͻͻͻͻΨ
ͳǤͲͲͲͳ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͻͻΨ
the
ͲǤͲͲͲͳ ൅ ͳǤͲ ൌ ͳǤͲͲͲͳ

0.0001 molecule in base form + 1.0 molecule in acid form = 1.0001 total molecules
ൌ ൌ
ͲǤͲͲͲͳ
ൌ ൈ ͳͲͲΨ ൌ ͲǤͲͲͻͻͻͻΨ
ͳǤͲͲͲͳ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͻͻΨ
ͳǤͲͲͲͳ
question
The The question asksthe
asks for forpercent
the percent
that that willionized,
will be be ionized, so the
so the correct
correct answer
answer is
is ͻͻǤͻͻΨ.
99.99%.
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ሾ ሿ
ͺǤͷ ൌ ͳͲǤͷ ൅
ሾ ሿ
ሾ ሿ
െʹ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͳ ሾ ሿ

ͲǤͲͳ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This
ratio
This indicates that for
ratio indicates thatevery one molecule
for every thatthat
one molecule contains the the
contains functional group
functional in
group
the
ͲǤͲͳ ൅ ͳǤͲ ൌ ͳǤͲͳ
ൌ ൌ
ͲǤͲͳ
ൌ ൈ ͳͲͲΨ ൌ ͲǤͻͻΨ
ͳǤͲͳ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͲͳΨ
ͳǤͲͳ
the

ൌ ൌ
ͲǤͲͳ
ͳǤͲͳ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͲͳΨ
ͳǤͲͳ
The question
99.01%asks
. for the percent that will be ionized, so the correct answer is ͻͻǤͲͳΨ.
ሾ ሿ

ሾ ሿ
ሾ ሿ
ͺǤͷ ൌ ͳͲǤͷ ൅
ሾ ሿ

ሾ ሿ
െʹ ൌ
ሾ ሿ
ሾ ሿ ͲǤͲͳ ሾ ሿ

ͲǤͲͳ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
in the
This ratio acid (orthat
indicates unionized) form,
for every onethere is 0.01 that
molecule molecule that the
contains contains the functional
functional group in
group in the base (or ionized) form. The following equations can then be used
the to correctly calculate the percentage of the molecules that are ionized and the
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ͳǤͲͳ
the

ൌ ൌ
ͲǤͲͳ
ͳǤͲͳ
ͳǤͲ

ൌ ൈ ͳͲͲΨ ൌ ͻͻǤͲͲͳΨ
ͳǤͲͳ
0.99%.asks for the percent that will be ionized, so the correct answer is ͲǤͻͻΨ.
The question
REVIEW QUESTIONS
Drug (pKa value) Name of Functional Group Acidic/Basic

Acetaminophen (9.7) Phenol Acidic
Naproxen (4.2) Carboxylic acid Acidic
Baclofen (5.4) Carboxylic acid Acidic
Baclofen (9.5) Primary amine Basic
Dyclonine (8.2) Tertiary amine Basic
(piperidine)
2. The acidic, basic, or neutral environments are provided below.
Saliva Stomach Duodenum Plasma Urine

(pH = 6.4) (pH = 2) (pH = 5.4) (pH = 7.4) (pH = 5.7)
Acidic Acidic Acidic Basic (nearly neutral) Acidic
3. Predominant ionization states are provided below.
Saliva Stomach Duodenum Plasma

Drug (pKa value) (pH = 6.4) (pH = 2) (pH = 5.4) (pH = 7.4)
Acetaminophen (9.7) Unionized Unionized Unionized Unionized
Naproxen (4.2) Ionized Unionized Ionized Ionized
Baclofen (5.4) Ionized Unionized 50% ionized/50% unionized Ionized
Baclofen (9.5) Ionized Ionized Ionized Ionized
Dyclonine (8.2) Ionized Ionized Ionized Ionized

4. Baclofen contains an acidic functional group (carboxylic acid; pKa 5.4), and it will
be predominantly ionized when the environmental pH > pKa. As stated in the
chapter text, the Rule of Nines can be used in lieu of the Henderson-Hasselbalch
equation if the difference between the pH and pKa is an integer, as it is in this
scenario. Using this rule we can calculate the approximate percent ionization in
each of these environments (duodenum pH = 5.4; saliva pH = 6.4; plasma pH =
7.4) by simply determining the magnitude of the difference between the pH and
pKa. In the duodenum, the pH = pKa and, therefore, 50% of the carboxylic acid
will be ionized at any given time and 50% will be unionized. In the saliva, the
difference between the pH and the pKa values is 1; therefore, 90% of the carboxylic
acid functional groups will be ionized and 10% will be unionized. In the plasma,
the difference between the pH and the pKa values is 2; therefore, 99% of the
carboxylic acid functional groups will be ionized and 1% will be unionized.
5. Part A: Qualitative Approach (predominantly ionized or unionized?)
Naproxen contains a carboxylic acid (acidic; pKa = 5.4) in an environment pH = 7.4.

For acids, if pH > pKa, then the functional group is predominantly ionized.

Dyclonine contains a tertiary amine (piperidine) (basic; pKa = 8.2) in an environment
pH = 7.4. For basic functional groups, if the pH < pKa, then the functional group is
predominantly ionized.
REVIEW QUESTIONS
REVIEW QUESTIONS
B:Part
Part B: Quantitative
Quantitative Approach
Approach (% ionized
(% ionized andand % unionized?)
% unionized?)
Part B: Quantitative Approach (% ionized and % unionized?)

AnswerAnswer
for thefor the Acidic
Acidic Functional
Functional GroupGroup (Naproxen):
(Naproxen):
Answer for the Acidic Functional Group (Naproxen):
The form of the Henderson-Hasselbalch equation used for acidic functional groups
is shown below.
[Unprotonated Form] [Basic Form]
pH pK a log[Unprotonated Form] or pH = pK a + log [Basic Form]
pH pK a log [Protonated Form] or pH = pK a + log [Acidic Form]
[Protonated Form] [Acidic Form]
When using this equation to determine whether the functional group is

When using this ionized
predominantly equationor to determine
unionized, whether
we need the functional
to know the pKa of group is predominantly
the functional
When using this equation to determine whether the functional group is predominantly
group (carboxylic acid in naproxen pKa = 4.2) and the pH of the environment
(plasma pH = 7.4).
[Unprotonated Form]
7.4 4.2 log[Unprotonated Form]
7.4 4.2 log [Protonated Form]
[Protonated Form]
[Unprotonated Form]
3.2 log[Unprotonated Form]
3.2 log [Protonated Form]
[Protonated Form]
The fact that the number on the left is positive indicates that the carboxylic acid is
predominantly in its unprotonated (basic, ionized) form at pH = 7.4.
TheTofact that thethe
determine number on the
percentage of left is positive
ionized indicates
and unionized that
drug in the carboxylic
the plasma, we acid is
need to calculate the antilog of both sides of this equation. In this case the
antilog of 3.2 is 1585. This means that for every one molecule that is protonated
1585 molecules in ionized
(unionized form + 1.0there
carboxylic molecule in unionized
molecules form = 1586 total molecules
1585 molecules in ionized formacid), are 1585
+ 1.0 molecule in unionized that are
form unprotonated
= 1586 total molecules
(ionized carboxylic acid). 1585 Molecules in Ionized Form
Percent of Molecules in Ionized Form =1585 Molecules in Ionized Form u
Percent of Molecules in Ionized Form = 1586 Total Molecules u
1586 Total Molecules
1585 Molecules in Unionized Form
Percent of Molecules in Unionized Form =1585 Molecules in Unionized Form u
Percent of Molecules in Unionized Form = 1586 Total Molecules u
[Unprotonated Form]
3.2 log
The fact that the number on the left [Protonated
is positive
APPENDIX:
Form]TO CHAPTER
indicates
ANSWERS that theQUESTIONS
carboxylic acid
507 is
Calculation of the percentage of ionized drug and unionized drug at pH = 7.4

1585 molecules in one
requires ionized form +step.
additional 1.0 molecule in unionized form = 1586 total molecules
1585 Molecules in Ionized Form
Percent1585
of Molecules in Ionized Form =
molecules in ionized form + 1.0 molecule in unionized u
form = 1586 total
molecules
1585 Molecules in Ionized Form Form
PercentPercent
of Molofecules
Molecules Form == 1585 Molecules in Unionizedu
in Ionized Form
in Unionized
u
1585 Molecules in Unionized Form
Percent of Molecules in Unionized Form = u
Answer for the Basic Functional Group (Dyclonine):
Answer for the Basic Functional Group (Dyclonine):
Answer
The form for the Basic
of the Functional Group (Dyclonine):
Henderson-Hasselbalch equation used for basic functional groups is
The form of the Henderson-Hasselbalch equation used for basic functional groups
The form of the Henderson-Hasselbalch equation used for basic functional groups is
is show below.
[Unprotonated Form]
pH = pK a log [Unprotonated Form]
pH = pK a log [Protonated Form]
[Protonated Form]
predominantly
When ionized or to
using this equation unionized, we need
determine to know
whether the pKa of the
the functional functional
group is predominantly
group (tertiary amine in dyclonine pKa = 8.2) and the pH of the environment
(plasma pH = 7.4).
[Unprotonated Form]
7.4 8.2 log
When using this equation to determine [Protonated Form] group is predominantly
whether the functional
[Unprotonated Form]
0.8 log
[Protonated Form]
[Unprotonated Form]
7.4 8.2 log
[Protonated Form]
The fact that the number on the left is negative indicates that the tertiary amine is
predominantly in its protonated [Unprotonated
(acidic, Form]at pH = 7.4.
ionized) form
0.8 log
Calculation of the percentage of ionized drug and unionized drug at pH = 7.4 requires
[Protonated Form]
To determine the percentage of ionized and unionized drug in the plasma, we
one additional step.
need to calculate the antilog of both sides of the equation. In this case, the antilog
of -0.8 is 0.16. This means that for every one molecule that is protonated (ionized
Calculation of the
tertiary amine) percentage
there of ionized drug
are 0.16 molecules andunprotonated
that are unionized drug at pH = 7.4
(unionized requires
tertiary
1 molecule
amine).
one in ionized
additional form + 0.16 molecules in unionized form = 1.16 total molecules
step.
Calculation of the percentage of ionized drug and unionized drug at pH = 7.4
requires one additional step.
ͲǤͳ͸
1 molecule in ionized form + 0.16 molecules in unionized form = 1.16 total molecules
ൌ ൈ ͳͲͲΨ ൌ ͳ͵Ǥ͹Ψ
1 molecule in ionized form + 0.16 molecule inͳǤͳ͸
unionized form = 1.16 total molecules
ͲǤͳ͸
ͳ
ͳǤͳ͸
ൌ ൈ ͳͲͲΨ ൌ ͺ͸Ǥ͵Ψ
ͳǤͳ͸
ͳ
ൌ ൈ ͳͲͲΨ ൌ ͺ͸Ǥ͵Ψ
ͳǤͳ͸
7. In order to determine if a drug can participate in an ionic interaction with the ionized
arginine
7. In order to determine if a drug can participate in an ionic interaction with the ionized
arginine Unauthenticated | Downloaded 07/13/21 09:53 AM UTC
VWHS
ͳ ൅ ͲǤͳ͸ ൌ ͳǤͳ͸
6. Based on ionization only (which allows for ion-dipole interactions with water),
acetaminophen is the only one of the four drugs that is unionized in the plasma.
Although this molecule can participate in other types of interactions with water
(e.g., H-bonding), it cannot participateͲǤͳ͸
in ion-dipole interactions because it is not

ionized in that environment.
ͳǤͳ͸
Based on ionization only (which allows for ion-dipole interactions with water),
baclofen is the only one of the four drugs that has two ionized functional groups in
the plasma. This molecule will be able toͳ
interact with water via both the ionized
ൌ acid.
primary amine and the ionized carboxylic ൈ ͳͲͲΨ ൌ ͺ͸Ǥ͵Ψ
ͳǤͳ͸
7. In order to determine if a drug can participate in an ionic interaction with the

ionized arginine residue found within the active site of COX-1, we first need
,QWKHDFWLYHVLWHRIF\FORR[\JHQDVH&2;WKHUHLVDQLRQL]HGDUJLQLQHUHVLGXHS+
to determine what the ionized form of arginine looks like at pH = 7.4. Using
the Henderson-Hasselbalch equation to determine if this functional group is
predominantly ionized in the plasma (pH = 7.4), we learn that 99.9991% of the
$QVZHUHQYLURQPHQWVHHVWUXFWXUHRILRQL]HGDUJLQLQHVLGHFKDLQEHORZ
molecules of arginine will be ionized in that environment (see structure of ionized
arginine side chain below).
For a drug to participate in an ionic interaction with the side chain of this arginine
residue, it must contain a functional group that is negatively charged in the 3DJHRI
same environment. Because we have already determined that naproxen will be
predominantly ionized at pH = 7.4 (via the carboxylic acid), it stands to reason that
naproxen can participate in this critical ionic interaction with the ionized arginine
residue.
Dyclonine contains a basic tertiary amine (piperidine) and when ionized will be
positively charged. As we determined in Question #5, dyclonine will be 86.3%
ionized in this environment (pH = 7.4). Since an ionic interaction requires that
an ion pair form between one negatively and one positively charged functional
group, it stands to reason that the positively charged tertiary amine (piperidine) in
dyclonine cannot participate in an ionic interaction with the positively charged side
chain of the arginine residue.

Functional Group Saliva Stomach Duodenum Plasma Urine

Name Acidic or Basic (pH = 6.4) (pH = 2) (pH = 5.4) (pH = 7.4) (pH = 5.7)
Tertiary amine Basic Ionized Ionized Ionized Ionized Ionized
(piperidine) (pKa=9-11)
'HWHUPLQHWKHHQYLURQPHQWDOS+WKDWLVQHFHVVDU\IRUDFHWDPLQRSKHQWREHLRQL]HG
Carboxylic acid Acidic Ionized Unionized Ionized Ionized Ionized
(pKa=2.5-5)
$QVZHU7KHIRUPRIWKH+HQGHUVRQ+DVVHOEDFKHTXDWLRQXVHGIRUDFLGLFIXQFWLRQDOJURXSVLVVKRZQ
There are no physiological environments in which fexofenadine is predominantly
EHORZ
in its unionized form. In order for the drug to be absorbed via passive diffusion,
we can see that in the stomach the carboxylic acid will primarily be in its unionized
form; however, onlyሾ୙୬୮୰୭୲୭୬ୟ୲ୣୢ୊୭୰୫ሿ
a very, very small fraction of the tertiary ሾ୆ୟୱ୧ୡ୤୭୰୫ሿ
amine (piperidine)
ൌ ൅ RU ൌ ୟ ൅
will be in itsୟunionized form in that environment at any
ሾ୔୰୭୲୭୬ୟ୲ୣୢ୊୭୰୫ሿ givenሾ୅ୡ୧ୢ୧ୡ୤୭୰୫ሿ
time. We know that
an equilibrium exists between the unionized and ionized form of the drug and
that the equilibrium will be re-established as ሾͷሿthe unionized drug is absorbed, so
ൌ ͻǤ͹ ൅
ሾͻͷሿ
we might anticipate that little by little fexofenadine will be absorbed from the
stomach.
&LSURIOR[DFLQLVDQDQWLEDFWHULDODJHQWWKDWLVIRUPXODWHGDVDVROXWLRQZLWKGH[DPHWKDVRQH
9. Part A: Acidic and basic functional groups and their respective pKa values are
shown below.
$ &RQVLGHUDOORIWKHDFLGLFDQGEDVLFIXQFWLRQDOJURXSVIRXQGZLWKLQWKHVWUXFWXUHRI
$QVZHU
S.D DFLGLF
S.D EDVLF
&LSURIOR[DFLQ
Part B: The hydrochloride salt form of the drug is ionized (amine is in its
protonated form) and, therefore, is capable of participating in an ion-dipole
interaction with water. This enhances the solubility of the drug in an aqueous
% ,QWKLVIRUPXODWLRQFLSURIOR[DFLQLVSUHVHQWDVDK\GURFKORULGHVDOW0RGLI\WKHVWUXFWXUH
solution.
&O

3DJHRI
Part C:
Answer
forC:Acidic Functional Group (Carboxylic Acid)
Part
The form of
Answer forthe Henderson-Hasselbalch
Acidic equation Acid)
Functional Group (Carboxylic used for acidic functional groups is

shown below.
The form of the Henderson-Hasselbalch equation used for acidic functional groups
is shown below.
[Unprotonated Form] [Basic form]

pH = pK a log or pH = pK a log
[Protonated Form] [Acidic]
predominantly
When ionized orto
using this equation unionized,
determinewe whether
need to know the pKa of group
the functional the functional
is predominantly
group (carboxylic acid in ciprofloxacin pK = 6) and the pH of the environment
a
(formulation pH = 5).
[Unprotonated Form]
5 6 log
[Unprotonated Form]
5 6 log [Protonated Form]
[Protonated
When using this equation to determine Form]
whether the functional group is predominantly
[Unprotonated Form]
1 log
[Unprotonated Form]
[Unprotonated Form]
log [Protonated Form]
51 6 log
[Protonated
[Protonated Form]
Form]
The fact that the number on the left is negative indicates that the carboxylic acid is
predominantly in its protonated (acidic, unionized) form at pH = 5.
To determine the percentage of ionized and unionized
[Unprotonated Form] drug in the formulation, we
To To determinethe
determine 1 of
thepercentage
percentage logionized
of ionized and
andunionized
unionizeddrug
drugin in
thethe
formulation, we we
formulation,
needneed to calculate the antilog of both [Protonated Form]
sides of this equation. In this case, the antilog
need
of −1 is 0.1. This means that for every one molecule that is protonated (unionized
carboxylic acid; acidic) there is 0.1 molecule that is unprotonated (ionized
To determine
carboxylic acid;the percentage of ionized and unionized drug in the formulation, we
basic).
0.1 molecules in ionized form + 1.0 molecule in unionized form = 1.1 total molecules
0.1
molecules
need inofionized
Calculation form + 1.0
the percentage of molecule in unionized
ionized drug formdrug
and unionized = 1.1
at total
pH =molecules
5
0.1 Molecules in Ionized Form
Percent of Molecules in Ionized Form = u 100% 9.09%
0.1 molecules
0.1of
molecule in ionized
in ionized form
form ++ 1.0 0.1 Molecules
1.0 molecule
molecule
1.1
in Total in
in unionized
unionizedIonized Form
form == 1.1
Molecules
form 1.1 total molecules
total molecules
Percent Molecules in Ionized Form = u 100% 9.09%
1.1 Total Molecules
0.1
0.1Molecules in Ionized
Molecule in
1 Molecule in Ionized FormForm
Form
Unionized
Percent
Percent of Molecules
of Molecule in Ionized Form
s in Unionized Form== u 100% 9.09%99.9%
u 100%
1.1 Total in
1 Molecule Molecules
Unionized Form
Percent of Molecules in Unionized Form = 1.1 Total Molecules u 100% 99.9%
1.1 Total Molecules
1 Molecule in Unionized Form
Percent of Molecules in Unionized Form = u 100% 99.9%
90.9%
Answer for Basic Functional Group (Secondary 1.1 Total Molecules
Amine/Piperazine)
Answer for Basic Functional Group (Secondary Amine/Piperazine)
Answer for Basic Functional Group (Secondary Amine/Piperazine)
The form
Answer forof theFunctional
Basic Henderson-Hasselbalch
Group (Secondaryequation used for basic functional groups is
Amine/Piperazine)
The form of the Henderson-Hasselbalch equation used for basic functional groups
is show below. [Unprotonated Form]
pH pH a log
[Unprotonated Form]
pH pH a log [Protonated Form]
pH pH log
[Protonated Form]
[Unprotonated Form]
a
[Protonated Form]
[Unprotonated Form]
[Unprotonated Form]
pH pH a log
[Protonated
APPENDIX: Form]
ANSWERS TO CHAPTER QUESTIONS 511

predominantly
When ionized orto
using this equation unionized,
determinewe whether
need to know the pKa of group
the functional the functional
is predominantly
group (secondary amine in ciprofloxacin pKa = 8.8) and the pH of the environment
(formulation pH = 5).
[Unprotonated Form]
5 8.8 log
[Protonated Form]
[Unprotonated Form]
3.8 log
[Protonated Form]
The fact that the number on the left is negative indicates that the secondary amine
is predominantly in its protonated (acidic, ionized) form at pH = 5.
To determine the percentage of ionized and unionized drug in the formulation, we

need to calculate the antilog of both sides of the equation. In this case, the antilog
of −3.8 is 0.000158. This means that for every one molecule that is protonated
(ionized secondary amine), there are 0.000158 molecules that are unprotonated
(unionized secondary amine).
Calculation of the percentage of ionized drug and unionized drug at pH = 5 requires
Calculation of the percentage of ionized drug and unionized drug at pH = 5
one
1 molecule in ionized form + 0.000158 molecule in unionized form = 1.000158 total molecules

Percent of Molecules in Unionized Form = u 100% 0.016%
1.000158 Total Molecules
1 Molecule in Ionized Form

Percent of Molecules in Ionized Form = u 100% 99.98%
1.000158 Total Molecules

CHAPTER 5
CHAPTER
STRUCTURE ANALYSIS5CHECKPOINT
STRUCTURE
Checkpoint ANALYSIS CHECKPOINT
Drug 1: Venetoclax
CHAPTER 5
1. The Checkpoint Drug
potassium salt 1: Venetoclax
of venetoclax is shown below.
1. The potassium salt of venetoclax is shown below.
1. The potassium salt of venetoclax is shown below.
-
Part A: In Chapter 3, we identified five ionizable functional groups. Four of these

five functional groups are basic, while one is acidic. In order to form a salt, it is
necessary to combine an acid and a base in a solution. In this case, an inorganic
Partpotassium
B: Shownsalt was formed,
below so it cansalt
is a diolamine be of
concluded that Another
venetoclax. the potassium
base ion
thatcame
could be used
from KOH, a strong inorganic molecule. The addition of KOH to a solution
containing
to make a saltvenetoclax will cause a significant
with the sulfonamide increase in the pH of the solution.
is tromethamine
All four basic functional groups will be primarily unionized, while the acidic
sulfonamide will be primarily ionized. Under these conditions, the negatively
Part B: charged
Shown below is a diolamine
sulfonamide salt of
will react with thevenetoclax. Another
positively charged base that
potassium to could be used
form the
salt shown in the answer to question 1.
to make a salt with the sulfonamide is tromethamine
Part B: Shown below is a diolamine salt of venetoclax. Another base that could be
used to make a salt with the sulfonamide is tromethamine
Venetoclax diolamine
Venetoclax diolamine

Part C: Water-soluble organic salts are able to provide enhanced solvation and
dissolution as compared to inorganic salts. The inorganic potassium ion is able to
form ion-dipole bonds with water (as the ion). This is also true with the nitrogen
atom of diolamine salt; however, the two hydroxyl groups allow additional
hydrogen bonds with water, thus further enhancing water solubility beyond what is
possible with the potassium salt.
2. The structure of venetoclax contains a large number of functional groups that

can form hydrogen bonds or ion-dipole interactions with water. These have been
highlighted below. Please note that the tertiary amine and the sulfonamide (boxed)
will be primarily ionized in the pH of the small intestine and would participate in
ion-dipole interactions with water. These functional groups provide sufficient water
solubility for venetoclax to dissolve in the gastrointestinal (GI) tract. The remaining
functional groups (aromatic and alicyclic rings, alkyl chains, and halogens) provide
Page 37, Question
sufficient lipid2solubility to allow venetoclax to traverse the GI membrane once it is
dissolved.
hydrogen ion-dipole
ion-dipole bond hydrogen bond
interaction
interaction acceptor donor and acceptor
hydrogen
bond
acceptor
ion-dipole
interaction
hydrogen
bond
acceptor
hydrogen
bond
hydrogen acceptor
bond
donor
3. As compared to the original structure of venetoclax, the addition of a hydroxyl

group enhances water solubility due to the fact that this functional group can
form hydrogen bonds with water. Additionally, the addition of a hydroxyl group
allows for the formation of water- and lipid-soluble ester prodrugs. As discussed
in the Chapter, esterases are ubiquitous throughout the human body, allowing the
release of the active drug in the liver, the blood stream, the GI tract, or the target
tissue.

4. The chlorine group is lipid soluble; therefore, removing it and replacing it with
a hydrogen atom would decrease the overall lipid solubility, or increase the
overall water solubility, of venetoclax. Additionally, because the chlorine group
ion-d
is electron withdrawing through induction, the aromatic ring would no longer
intera
hydrogen
be electron deficient. This could affect charge transfer interactions and other
bond
interactions between the aromatic ring and its biological target. A full explanation
of these types of interactions is provided in the next chapter. Additionally, acceptor
electron
withdrawing groups on aromatic rings decrease the metabolic oxidation of the
hydrogen
ring. This will be discussed in Chapter 8. Finally, since a hydrogen atom is smaller
than a chlorine atom, the para position of thishydrogen bond
aromatic ring would be less sterically
hindered. acceptor
bond
donor

Checkpoint
1. Part A: Elamipretide Drug
can be 2: Elamipretide
formulated as a sodium or potassium salt (phenol) or
as a hydrochloride or hydrobromide salt (guanidine and primary amine).
Part B:
Part B: The hydrochloride salt of the primary amine of lysine is shown below.
The hydrochloride salt of the primary amine of lysine is shown below.
Cl-

The sodium salt of the phenol is shown below.
The sodium salt of the phenol is shown below.
H2N NH
N
H NH 2
H O H O
N N
H2N N NH 2
O H O
H 3C
C H3
O – Na+
Part C: When comparing the sodium salt of elamipretide with the parent drug, it is
important toREVIEW
note that QUESTIONS
the sodium salt will allow for an ion-dipole interaction with
water that will enhance the overall hydrophilic character of the drug molecule. This
will enhance water solubility
1. Parts A and and
B: therefore improve
Functional groups distribution
required toin the plasma.
form This been circle
salts have
will also translate into better solubility and dissolution of the sodium salt of the
drug when compared below.
to the parent drug.
2. Elamipretide is a molecule that is significantly ionized across a range of pH

values. The likelihood of it being water soluble at pH = 7.4 for IV administration
is fairly good. If you are concerned that the substituted phenol and the aromatic
hydrocarbon represent significant enough hydrophobic character to warrant
formation of a water-soluble organic salt, then consider formulation as a tartrate
salt (in Figure 5-3 there are other examples). Because elamipretide contains
several basic function groups (guanidine and two primary amines), it is possible to
formulate the drug as a lactate salt.
3. Part A: We know that the smaller the value of log P the more water soluble the
drug molecule is. In this case cLog P = 0.3677 for elamipretide and the cLogP
values for the HMGCoA reductase inhibitors are all larger than this value (although
rosuvastatin isn’t significantly larger!!). That means that elamipretide is likely to be
significantly more water soluble than the HMGCoA reductase inhibitors.
Part B: The structure evaluation conducted in Chapter 2 revealed that there is

significant hydrophilic character present in elamipretide (phenol [OH], primary
amines, guanidine, amides). This supports the small cLogP value that indicates that
elamipretide is water soluble.
Part C: There are several structural modifications that could be made to increase
the lipophilic character of elamipretide. A lipid-soluble salt (e.g., stearate) could
be formed with the basic functional groups. A lipid-soluble ester prodrug (e.g.,

benzoate) of the phenol could be developed. Converting the amino terminus

(primary amine) to an acetamide or other lipophilic amide is another option, but
only if this primary amine isn’t involved in a critical ionic interaction or ion-dipole
interaction (as the ionic component) with the biological target.
4. Part A: As mentioned in the answer to Question 3C, the amino terminus primary
amine group can be converted to a lipophilic amide to improve lipid solubility
of the drug molecule (provided that key ionic and/or ion-dipole interactions
with the amine are not required). This type of transformation also protects the
molecule from degradation from aminopeptidases, since the enzyme would no
longer recognize the drug molecule as a potential substrate. [Note—if the other
primary amine (side chain of lysine) was converted into a lipophilic amide, the
drug molecule would become more lipid soluble, but would still remain subject to
degradation via aminopeptidases.]
The one problem with this strategy is that amidases are not as ubiquitous
as esterases, and there is the potential that the amide would not undergo
bioactivation (hydrolysis) to form an appreciable amount of the component
carboxylic acid and amine (parent drug). My earlier warning about the types of
interactions that are required with this primary amine determine whether or not
the amide would represent a prodrug. Remember—a prodrug must be able to be
metabolically cleaved to produce the active drug!!!
Part B: Lipid-soluble ester prodrugs enhance the overall lipid solubility of the drug
molecule and, therefore, improve absorption across lipophilic members (e.g., GI
wall, skin, cell membranes). This will cause an increase in cLog P to reflect less
water solubility and more lipid solubility. This improved solubility will enhance
oral bioavailability. These types of prodrugs can also be used in depot-based
formulations, which increases the duration of action of the product administered.

&+$37(5

'LOWLD]HPLVPDUNHWHG
REVIEW QUESTIONS
1. Parts A and B: Functional groups required to form salts have been circled and
$QVZHUVIRUSDUWV$DQG%
modified below.
2&+ 2&+
6 6
2 2
2 2
1 1
2 2

1 1 + &O
'LOWLD]HP 'LOWLD]HPK\GURFKORULGH
2
± 1D
+2 3 2
32 +
32 +
32 + 2+
1
2+
1 5LVHGURQDWHVRGLXP
1RWHWKDWWKHVRGLXPVDOW
5LVHGURQDWH FDQEHIRUPHGZLWKHLWKHUSKRVSKDWH

Part C: The salts formed are both inorganic salts.

3DJHRI

2. Rasagiline mesylate and metoprolol mesylate are examples of organic salts. Each drug
has2.been modified below to represent the form present at pH = 7.4.
Rasagiline mesylate and metoprolol mesylate are examples of organic salts. Each
drug has been modified below to represent the form present at pH = 7.4.
+
H N CH3 SO3-
H
Rasagiline mesylate
OH H
H O
O N C H3
+ –
OH
O
H3 C C H3
O O
Metoprolol succinate
3. Part A: Answers are provided in the grid below.

4. Log P = –1 can be translated to mean for every one molecule that partitions into the
Hydrophilic and/or Acidic, Basic, or Contribution to Aqueous
Name of Functional Group Hydrophobic Neutral Solubility and/or Absorption
Ether(s) Hydrophilic (O) Neutral Aqueous solubility (O)
Hydrophobic (R) Absorption (R)
Aromatic hydrocarbon Hydrophobic Neutral Absorption
Tertiary amine Hydrophilic (N) Basic Aqueous solubility (N)
Hydrophobic (R) (ionized at pH = Absorption (R)
7.4)
Cycloalkene Hydrophobic Neutral Absorption
Secondary alcohol Hydrophilic (OH) Neutral Aqueous solubility (OH)
8. BothR of these
= carbon agents are very hydrophilic in character (acamprosate calcium: sulfonate salt,
scaffolding.
Part B:
Galatamine has a balance between functional groups that are hydrophobic

O
(aromatic hydrocarbon, cycloalkene) and can contribute to the abilityPO of the drug
–
O 3 H2
to be absorbed/cross lipophilic membranes and groups that are hydrophilic (ether,
S N alcohol,
secondary C H3 ionized
Ca+2
tertiary amine) that will allow for dissolution/solubility in +
O H PO3 H - Na
O
the aqueous contents of the stomach.
OH
2
Part C: Galantamine hydrobromide is more hydrophilicNdue to the presence of an
ionized functional group that can participate in strong ion-dipole interactions with
water.
Acamprosate calcium Risedronate sodium

4. Log P = –1 can be translated to mean for every one molecule that partitions into
the organic phase, there are 10 molecules that partition into the aqueous phase.
The more negative the value of log P, the more water soluble the drug is. When
you compare the log P values for oxytetracycline and doxycycline, you can see
that the number is becoming more positive, meaning the drug is becoming less
&RQVLGHUWKHWZRWHWUDF\FOLQHVGUDZQEHORZDQGWKHLUUHVSHFWLYHORJ3YDOXHV
water soluble. If you analyze the functional group composition of each $QVZHU
of these
tetracyclines, you will see that doxycycline contains one less hydroxyl group and
therefore is likely to be slightly less hydrophilic than oxytetracycline.
2[\WHWUDF\FOLQHORJ3 'R[\F\FOLQHORJ3
5. (DFKRIWKHWKUHHDJHQWVEHORZLVXVHGLQWKHWUHDWPHQWRISVRULDVLV
Part A: The structure evaluation is provided in the grid below.

Hydrophilic
and/or Contribution to Aqueous

Name of Functional Group Hydrophobic Acidic, Basic, or Neutral Solubility and/or Absorption
ACITRETIN

Aromatic Hydrocarbon Hydrophobic Neutral Absorption

Alkene Hydrophobic Neutral Absorption
Carboxylic acid Hydrophilic (COOH) Acidic Aqueous Solubility (COOH)
$FLWUHWLQ
CALCIPOTRIOL

Cycloalkane Hydrophobic Neutral Absorption
Alkene Hydrophobic Neutral Absorption

Secondary alcohol(s) Hydrophilic (OH) Acidic Aqueous Solubility (OH)
TAZAROTENE

Aromatic hydrocarbon Hydrophobic Neutral Absorption
Alkyne Hydrophobic Neutral Absorption

Azine (pyridine) Hydrophilic (N) Basic Aqueous Solubility (N)
7D]DURWHQH
Ester Hydrophilic (COO) Neutral Aqueous Solubility (COO)
Thiane (cyclic thioether) Hydrophobic Neutral Absorption
&DOFLSRWULRO
3DJHRI

Part B: Psoriasis is an autoimmune disease characterized by areas of inflammation

and excessive skin production. In the affected areas, skin accumulates rapidly
and forms plaques that are commonly silvery-white in color. Although typically
associated with the skin, in 10–15% of patients psoriasis can cause inflammation
in the joints as well (psoriatic arthritis). Topical application of a medication to treat
these plaques will allow for local treatment of only the affected areas and hopefully
prevent unnecessary systemic distribution.
Calcipotriol contains functional groups that are hydrophobic in character
(cycloalkane, alkene) that will contribute to absorption of the drug into the affected
skin and plaques. Tazarotene contains functional groups that are hydrophobic in
character (aromatic hydrocarbon, alkyne, thiane) that will contribute to absorption
of the drug into the affected skin and plaques.
Part C: Acitretin contains a mixture of hydrophilic (carboxylic acid, ionized at most

physiological pHs) and hydrophobic functional groups (aromatic hydrocarbon,
alkenes). This provides sufficient hydrophobic/hydrophilic balance to allow the
drug to be solubilized in the aqueous contents of the GI tract and then absorbed
across the lipophilic membrane of the GI tract.
Part D: Tazarotene contains functional groups that are hydrophobic in character

(aromatic hydrocarbon, alkyne, thiane) that will contribute to absorption of the
drug into the affected skin and plaques. Given that this agent has systemic side
effects, one can assume that this agent is able to cross the skin and enter systemic
circulation. The hydrophilic azine and ester contribute to the ability of the drug to
be solubilized in the plasma.
6. Part A: The structure evaluation is provided in the grid below
Contribution to Aqueous Solubility

Functional Group Name Hydrophilic and/or Hydrophobic and/or Absorption
NAFTIFINE (MARKETED AS HCL SALT)
Aromatic hydrocarbon Hydrophobic Absorption
Tertiary amine (basic, ionized at Hydrophilic (N) Aqueous solubility (N)
most physiological pHs) Hydrophobic (R) Absorption (R)
Alkene Hydrophobic Absorption
UNDECYLENIC ACID (MARKETED AS CALCIUM SALT [POWDER] OR ZINC SALT [CREAM])
Alkene Hydrophobic Absorption
Alkane Hydrophobic Absorption
Carboxylic acid (acidic, ionized at Hydrophilic (COOH) Aqueous solubility (COOH)
most physiological pHs) Hydrophobic (R) Absorption (R)
FLUCONAZOLE
Halogenated aromatic Hydrophobic (R) Absorption (R)
hydrocarbon
1,2,4 Triazole Hydrophilic (Ns) Aqueous solubility (Ns)
Tertiary alcohol Hydrophilic (OH) Aqueous solubility (OH)
N = nitrogen atoms; R = carbon scaffolding.

Part B: Naftifine and undecylenic acid contain several functional groups (e.g.,
aromatic hydrocarbon, alkene, aliphatic alkane) that contribute to the hydrophobic
character of these molecules. Because they are predominantly hydrophobic in
character, this allows for enhanced absorption across lipophilic membranes.
The therapeutic goal for these patients is to treat a fungal infection that is localized
on their feet; therefore, medication does not need to be administered systemically.
In order to be effective, the medication used must be able to penetrate both
the skin and the fungal cell wall, both of which have a hydrophobic component
associated with them.
Part C: For a drug to be given orally it must have hydrophilic character to allow
for solubility in the aqueous contents of the stomach and hydrophobic character
to allow for absorption across the lipophilic membranes of the GI tract. A balance
in these two types of structural characteristics is necessary for a drug to be
administered orally.
In fluconazole there is a halogenated aromatic hydrocarbon present. This

functional group is hydrophobic and will contribute to drug absorption. The
heteroatoms in the 1,2,4 triazole rings are hydrophilic in character, as is the
tertiary alcohol. These three functional groups contribute significantly to the water
solubility of this agent.
Part D: This agent contains ethers (several) and other oxygen containing functional
groups (ketones), all of which can interact with water via H-bonding (as H-bond
acceptors). This suggests that this agent has more hydrophilic character than
the antifungal agents (used topically) discussed above. Although there is a
halogenated aromatic hydrocarbon (chloro substituent) and a cycloalkene present
that will contribute to the hydrophobic character of the drug, this agent is poorly
absorbed across lipophilic membranes and is not utilized topically to treat fungal
infections.
7. Part A: Hydrocortisone sodium succinate is a water-soluble organic ester. This

increases the hydrophilic character of hydrocortisone sufficiently to become
water soluble enough to be administered IM or IV. The strategy utilized to allow
hydrocortisone to be administered IM or IV was via formation of a water-soluble
organic ester.
Part B: Hydrocortisone valerate is hydrophobic ester of hydrocortisone. This

structural change further increases the hydrophobic character of hydrocortisone
and decreases its aqueous solubility. Without sufficient balance between
hydrophilic and hydrophobic character, this agent is unlikely to be sufficiently
bioavailable if administered via an oral route and will not be soluble enough to
allow for IM or IV administration.

8. Both of these agents are very hydrophilic in character (acamprosate calcium:

sulfonate salt, amide; risedronate sodium: bisphosphonate, secondary alcohol,
pyridine) and are likely to be very water soluble. As a result, their elimination
8. Both of these
pathway agentsto
is unlikely are very hydrophilic
include in character
the need for Phase I or(acamprosate calcium: sulfonate salt,
Phase II metabolic
transformations.
O
–
O PO3 H2
S N C H3 Ca +2
- Na +
O H PO3 H
O
OH
2 N
Acamprosate calcium Risedronate sodium
9. The acidic or basic character of each drug is shown below.
Fentanyl citrate Fentanyl is basic.

Diphenhydramine hydrochloride Diphenhydramine is basic.
Fenoprofen calcium Fenoprofen is acidic.
Morphine sulfate Morphine is basic.
Clevidipine butyrate Clevidipine is basic.
Miconazole nitrate Miconazole is basic.
Pravastatin sodium Cromolyn is acidic.
Diclofenac potassium Diclofenac is acidic
10. Both vitamin E and vitamin A (in the form of retinol) are used in the management of skin
conditions,
10. Bincluding acne,
oth vitamin wound
E and vitaminhealing,
A (in theand the
form of effects
retinol) of
areaging.
used in the management
of skin conditions, including acne, wound healing, and the effects of aging.
C H3
C H3
H3C O
C H3
3
HO C H3
C H3
Vitamin E Vitamin A
Part A: We know that the partition coefficient of a drug molecule is defined

as the ratio of the solubility of the unionized drug in an organic solvent to the
solubility of the same unionized drug in an aqueous environment. Log P = 1 can
be translated to mean for every 10 molecules that partition into the organic phase,
there is 1 molecule that partitions into the aqueous phase. The more positive the
value of log P, the more lipid soluble the drug is. In this case, both vitamin A and
vitamin E have cLogP values that are much larger than one, which means that they

are very hydrophobic in character. Administration of a drug molecule (or in this

case a vitamin) via the skin requires that the drug/vitamin possess considerable
hydrophobic character in order for it to be absorbed into and potentially across
the lipophilic skin.
Part B:
1. Vitamin E contains an ionizable phenol functional group. This group can be

converted into an inorganic salt (e.g., potassium salt) that can participate in an
ion-dipole interaction with water and therefore enhance the aqueous solubility
of the vitamin. Vitamin E could also be modified to form a water-soluble
organic salt (e.g., a tromethamine salt). Again, the ionized drug can participate
in an ion-dipole interaction with water and, therefore, enhances the aqueous
solubility of the vitamin.
2. Vitamin A does not contain an ionizable functional group, so it cannot form

inorganic salts or a water-soluble organic salt. It can, however, be formulated
as a water-soluble prodrug (e.g., sodium succinate ester) that can be
metabolically cleaved to the parent vitamin. In this case, the inactive vitamin
prodrug is able to participate in the ion-dipole interactions with water to
improve the water solubility of the prodrug, and then metabolic hydrolysis
will release the less aqueous soluble vitamin. Another option is to oxidize
the primary alcohol to the corresponding carboxylic acid and then form an
inorganic salt that will confer additional aqueous solubility. In this scenario, the
carboxylic acid form of the vitamin represents one of the active forms of the
vitamin and represents most of the activity of vitamin A.

CHAPTER 6
1. Answers provided in the table below.
Amino Acids Capable of Forming Specific

Functional Group Types of Binding Interactions Binding Interaction
A Halogenated phenyl (1) van der Waals; Hydrophobic (1) Tyr, Phe, Trp (better interaction)*; Val, Leu,
ring (or aromatic ring) Ile, Met, Ala
(2) π-π Stacking (2) Tyr, Phe, Trp
(3) Charge Transfer (as electron (3) Tyr, Trp
poor aromatic ring)
(4) Cation-π Interactions (4) Lys, Arg, His**
B Tertiary amine (1) Ionic (1) Asp, Glu
(2) Ion-Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln
C Sulfonamide*** (1) Ionic (1) Lys, Arg, His**
(2) Ion-Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His**
D Heterocyclic non- Ether oxygen
aromatic ring (1) Ion-Dipole (as the Dipole) (1) Lys, Arg, His**
(ether containing (2) Dipole-Dipole (2) Asn, Gln
alicyclic ring)
(3) Hydrogen Bond (Acceptor) (3) Ser, Thr, Tyr, Trp, Cys, Asn, Gln, His**
Hydrocarbon ring Val, Leu, Ile, Met, Ala (better interaction)*; Tyr,
van der Waals; Hydrophobic Phe, Trp
*
Stronger van der Waals interactions occur when aromatic rings interact with aromatic rings and when aliphatic rings
and chains interact with aliphatic rings and chains; however, all of the listed amino acids could possibly interact with
the indicated functional groups.
**
The side chain of histidine is primarily unionized at a pH =7.4. The small fraction that is ionized could participate in a
cation-π interaction or an ionic bond, while the unionized fraction can serve as a dipole in an ion-dipole interaction or
as a hydrogen bond donor or acceptor.
The carbonyl group has been included in the box because it provides additional resonance delocalization of the
***
negative charge of the sulfonamide (see Chapter 3 Questions/Answers).

Functional Group Types of Binding Possible with DNA (Yes or No) and Why or Why
Interactions Not.
A Halogenated phenyl ring (1) van der Waals; (1) Yes, the purine and pyrimidine rings have a
(or aromatic ring) Hydrophobic dipole, so dipole-induced dipole interactions are
possible. Hydrophobic interactions are less likely
due to the normal stacking of DNA bases (i.e., less
displacement of water).
(2) π-π Stacking (2) Yes, this could occur with the purine and
pyrimidine bases.
(3) Charge Transfer (as (3) Yes, this could occur with the purine and
electron poor aromatic ring pyrimidine bases.
(4) Cation-π Interactions (4) No, positive charges are not normally present
in DNA
B Tertiary amine (1) Ionic (1) Yes, ionic bonds could form with the phosphate
groups of DNA.
(2) Ion-Dipole (as the Ion) (2) Yes, this could occur with dipoles present in
the purine and pyrimidine bases as well as the
deoxyribose sugar.
C Sulfonamide (1) Ionic (1) No, positive charges are not normally present
in DNA.
(2) Ion-Dipole (as the Ion) (2) Yes, this could occur with dipoles present in
the purine and pyrimidine bases as well as the
deoxyribose sugar.
D Heterocyclic non-aromatic Ether oxygen

ring (1) Ion-Dipole (as the (1) Yes, this could occur with dipoles present in
(ether-containing alicyclic Dipole) the purine and pyrimidine bases as well as the
ring) deoxyribose sugar.
(2) Dipole-Dipole (2) Unlikely, but could occur with partially positive
carbon atoms in the purine and pyrimidine bases
(3) Hydrogen Bond (3) Yes, hydrogen bond donors exist in purine and
(Acceptor) pyrimidine rings as well as the deoxyribose sugar.
Hydrocarbon ring No, these interactions generally occur with alicylic

van der Waals; Hydrophobic rings and chains, not the heterocylic bases in DNA.
2. Yes, it is possible for venetoclax to form covalent bonds with proteins, enzymes,
and other biomolecules; however, the probability of this occurring is somewhat
low. None of the functional groups present within the structure of venetoclax are
inherently highly reactive; thus, alkylation, acylation, or phosphorylation reactions
would not be expected to occur. It is, however, possible for one or more of these
functional groups to be metabolically transformed to a more highly reactive
intermediate similar to the rearrangement reactions discussed in the chapter. If this
were to occur, then a covalent bond could be formed.

Amino Acid Whose Side Chain

Functional Interactions Possible Interactions Possible Can Interact with the Functional
Group Name (as drawn) (at pH=7.4) Group at pH=7.4
A Guanidine 1. Hydrogen bonding 1. Ionic 1. Glu, Asp
(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the ion) 2. Ser, Thr, Tyr, Cys, Gln, Asn
B Primary amine 1. Hydrogen bonding 1. Ionic 1. Glu, Asp

(acceptor and donor)
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the ion) 2. Ser, Thr, Tyr, Cys, Gln, Asn
C Amide 1. Hydrogen bonding 1. Hydrogen bonding 1. Ser, Thr, Met, Tyr, Cys, Gln,
(acceptor and donor) (acceptor and donor) Asn, Trp, His
2. Ion-dipole (as the 2. Glu, Asp, Lys, Arg

2. Ion-dipole (as the dipole) dipole)
D Phenol 1. Hydrogen bonding 1. Hydrogen bonding 1. Ser, Thr, Met, Tyr, Cy, Gln, Asn,
(acceptor and donor) (acceptor and donor) Trp, His
2. Ion-dipole (as the dipole) 2. Ion-dipole (as the 2. Glu, Asp, Lys, Arg
dipole)
Interaction Type Functional Groups

Cation-π D
Ionic A, B
Chelation A, B
van der Waals D
Ion-dipole (as the dipole) C, D

REVIEW QUESTIONS
&+$37(5 Amino Acids Whose Side

Ionized,
Chain Can Interact with
Acidic, Basic, Unionized or Hydrogen Bond the Functional Group via
Name of or Neutral not Ionizable Acceptor, Donor, Hydrogen Bonding (at pH
$UIRUPRWHUROLVDȕ
Functional UHFHSWRUDJRQLVWWKDWLVDORQJDFWLQJEURQFKRGLODWRU(YDOXDWHWKH
Both, or Neither = 7.4). None Is a Possible
Group (As Drawn) (at pH = 7.4) (at pH = 7.4) Answer.
Amide Neutral Not ionizable Both Serine, Threonine, Tyrosine,
Cysteine, Asparagine,
Glutamine, Tryptophan,
Histidine, Methionine
Phenol Acidic Unionized Both Serine, Threonine, Tyrosine,
Secondary Neutral Not ionizable Both Serine, Threonine, Tyrosine,
Alcohol Cysteine, Asparagine,
$UIRUPRWHURO Glutamine, Tryptophan,
Secondary Basic Ionized Neither None
Amine
Ether Neutral Not ionizable Acceptor
Serine, Threonine, Tyrosine,
7KHVHFRQGDU\DOFRKRODQGWKHSKHQRO2+JURXSFDQSDUWLFLSDWHLQK\GURJHQERQGLQJZLWKWKH
Histidine
$QVZHU
2. Hydrogen bonding interactions with the hydroxyl groups are shown below.
2 &
2 1+
+
$VQ + δ−
1 1
+ $VQ
+ δ+
+ 1 &2 δ−
2
2+
2+ δ+
1
) 2
)
(]HWLPLEH
3DJHRI
3. Possible interactions are provided in the grid below.
H-bond
Acidic, Acceptor, Interaction Interaction Interaction Interaction
Name of Basic, Donor, Both, Possible with Possible with Possible with Possible with
Functional Neutral or Neither Serine Glutamic Acid Lysine Tryptophan (at
Group (As Drawn) (at pH = 7.4) (at pH = 7.4) (at pH = 7.4) (at pH = 7.4) pH = 7.4)
ERTAPENEM
Amide Neutral Both Hydrogen Ion dipole Ion dipole Hydrogen
(mono bonding; Drug = Drug = bonding;
substituted) dipole-dipole dipole dipole dipole-dipole
Amide Neutral Acceptor Hydrogen Ion-dipole Ion-dipole Hydrogen
(Lactam) only bonding; Drug = Drug = bonding;
dipole-dipole dipole dipole dipole-dipole
Carboxylic Acidic Neither Ion-dipole None Ionic Ion-dipole
acid pKa 2.5–5 (ionized) Drug = ion Drug = ion
Secondary Neutral Both Hydrogen Ion-dipole Ion-dipole Hydrogen
alcohol bonding; Drug = Drug = bonding;
dipole-dipole dipole dipole dipole-dipole
Thioether Neutral Acceptor Hydrogen None None Hydrogen
only bonding bonding;
Hydrophobic
interaction
Secondary Basic Neither Ion-dipole Ionic None Ion dipole
amine pKa (ionized) Drug = Ion Drug = ion;
(pyrrolidine) Cation-π
9–11
interaction
Aromatic Neutral Neither None None Cation-π Hydrophobic

hydrocarbon interaction interaction; π-π
stacking
Interaction Possible Name of One Amino Acid That Can

Name of Acidic, Hydrogen Bond with the Estrogen Participate in the Interaction Identified
Functional Basic, or Acceptor, Donor, Receptor (assume in the Previous Column with the
Group Neutral Both, or Neither pH=7.4) Functional Group (assume pH = 7.4)
Tertiary Basic Acceptor Ion-dipole Ser, Thr, Tyr, Cys, Asn, Gln, His, Trp (as
Amine (Drug = ion) dipole)
Ionic Asp, Glu
Cation-π interaction Phe, Tyr, Trp
Ether Neutral Acceptor Hydrogen Bonding Ser, Thr, Tyr, Cys, Asn, Gln, His
(Acceptor)
Dipole-Dipole
Ion-dipole Lys, Arg, Asp, Glu
(Drug = dipole)
Alkene Neutral Neither Hydrophobic Val, Leu, Ile, Phe, Met, Tyr, Trp
Halogenated Neutral Neither Hydrophobic Val, Leu, Ile, Phe, Tyr, Met, Trp
Aliphatic
Hydrocarbon
Aromatic Neutral Neither Hydrophobic; π-π Phe, Tyr, Trp, His (unionized form)
Hydrocarbon stacking
Cation-π interaction Lys, Arg, His (ionized form)

3UHGQLVRQHWROYDSWDQDQGGHPHFORF\FOLQHDUHDOODGPLQLVWHUHGRUDOO\7KLVPHDQVWKDWWKH\
5. Some sample interactions are shown below. Please note that prednisone and
demeclocycline contain additional hydroxyl groups and carbonyl groups that could
$QVZHU6RPHVDPSOHLQWHUDFWLRQVDUHVKRZQEHORZ3OHDVHQRWHWKDWSUHGQLVRQHDQGGHPHFORF\FOLQH
undergo similar types of hydrogen bonds.
+
+ δ
+
2
+ δ− +\GUR[\OJURXS
2 +ERQGGRQRU
2
2
2+
Replacement Structures δfor

+
Appendix Proof Pages (Pages 48-End)
+ 2
Page 53: The functional group δ−
2 on demeclocycline is incorrect. It is fixed below.
+ 3UHGQLVRQH
.HWRQH
+ERQGDFFHSWRU
Sulfonamide
G H-bond donor Phenol group
G G H-bond acceptor
6XOIRQDPLGH +
2
δ− + +ERQGGRQRU +\GUR[\OJURXS
+ 2 δ+ + +ERQGDFFHSWRU G
+δ
+ +
G
2
1
2
6G + + G +
G 2 2 2+ 2 2 δ−
δ− 2+
2 Amide
+
Fluorine ) H-bond
1 donor
δ+ δ+
1 δ−
H-bond acceptor +
2 +
2 2+ $PLGH
Tolvaptan +ERQGGRQRU
+& )OXRULQH + Demeclocycline
&O 2+ 1
+ERQGDFFHSWRU +& & +
7ROYDSWDQ
'HPHFORF\FOLQH
6. Part A: An ionic interaction occurs between the ionized carboxylic acid found in

the side chain of aspartic acid and the ionized primary amine found in the structure
Pageof82,dopamine.
Question 7: Replacement figure for tetrahydrocanibinol

Part B: The serine hydroxyl group is a neutral functional group and is not ionizable
in any physiological environment. The catechol is acidic in character and at
C
physiological pH (pH=7.4) the pH < pKa and the catechol will be unionized. Both
of these functional groups are able to participate in hydrogen bonding or dipole-
dipole interactions.
B 3DJHRI
4
3 A

F
Tetrahydrocannabinol
D: not a requirement; not present

E: not a requirement; not present


$QVZHU

$QVZHU
70,,
70,,,
70,,
70,,,
70,
70,9
70,
70,9
709,,
709,,
709,
709
709,
709

7. The positively charged zinc atom complexes with the lone pair of electrons on the
imidazole ring. Although the zinc atom can also complex with an amide carbonyl
found on the peptide backbone of insulin, it is much more likely to complex with
,QWKHSUHVHQFHRI]LQFLQVXOLQIRUPVDYHU\VWDEOHLQDFWLYH]LQFLQVXOLQKH[DPHU:LWKLQWKLV
the histidine side chain because this side chain is less sterically hindered and thus
more available.
,QWKHSUHVHQFHRI]LQFLQVXOLQIRUPVDYHU\VWDEOHLQDFWLYH]LQFLQVXOLQKH[DPHU:LWKLQWKLV
SHSWLGHEDFNERQH

RILQVXOLQ
SHSWLGHEDFNERQH =Q
RILQVXOLQ
=Q


Amino Acid Side Chain with Cetirizine
Possible Binding Interactions
Box 1 Glutamine Unionized amines: Dipole-dipole; hydrogen bonding (amino acid side chain = donor
or acceptor) 3DJHRI
Ionized amines: Ion-dipole (drug = ion); 3DJHRI
Box 2 Tyrosine Hydrophobic interactions; π-π interactions; van der Waals
Unionized amine: Dipole-dipole; hydrogen bonding (amino acid side chain is the
donor)
Ionized amine: Ion-dipole (drug = ion); Cation-π interaction
Box 3 Serine or Threonine Unionized carboxylic acid: Dipole-dipole; hydrogen bonding (drug = donor or
acceptor)
Ionized carboxylic acid: Ion dipole (drug = ion)
Box 4 Arginine or Lysine Ionized arginine (or lysine) and carboxylic acid: ionic
Ionized arginine (or lysine): ion-dipole (with the ether) (amino acid side chain = ion)

9. The dihydropyridine ring system found in the center of this molecule is largely
hydrophobic in character; however, it is unlikely to participate in van der Waals
or hydrophobic bonding interactions. There are five substituents attached to the
five carbons associated with this ring system. Three of the substituents are polar
in nature (two esters and an ether) and, although hydrophobic, the halogenated
aromatic hydrocarbon represents significant steric hindrance.
Formation of van der Waals interactions requires that the dihydropyridine is in
close proximity with another hydrophobic functional group. The halogenated
aromatic hydrocarbon is likely to create sufficient steric hindrance to prevent this
type of interaction to occur.
The polar nature of the three dihydropyridine substituents will likely interfere with
the formation of hydrophobic bonding interactions. As stated in the chapter, when
there is a polar region within a drug molecule, it is unlikely that the biological
target will contain complementary nonpolar functional groups.
Distance Requirement
(r = Distance Between Functional Groups) Strength of Interaction
Ionic 1/r 5–10 kcal/mol (strong)
Ion-dipole 1/r 2
4–5 kcal/mol
(functional groups need to be closer together
than in an ionic interaction)
Dipole-dipole and 1/r3 1–7 kcal/mol (intermediate)
hydrogen bonding (functional groups need to be closer together (hydrogen bonding
than in an ion-dipole interaction) 3–4 kcal/mol)
van der Waals 1/r4–1/r6 0.5–1 kcal/mol (weak)
and hydrophobic (functional groups need to be closer together
interactions than in a dipole-dipole interaction)
11. Drug molecules that covalently bind to their biological targets demonstrate
enhanced selectivity for their targets and a prolonged duration of action. Let’s look
at each of these properties individually. The enhancement in selectivity is primarily
achieved via the use of prodrugs that are converted to reactive intermediates
(active drug) in close proximity to their biological targets. Proximity of the reactive
intermediate and the biological target is important to maximize so as to avoid
unnecessary misadventures between the reactive intermediate and other proteins
present. In fact, it should be noted that those drugs that bind covalently that are
not prodrugs and therefore do not require in vivo bioactivation, are generally
no more selective than analogous drugs that interact via noncovalent means.
Although drugs that form a covalent bond with their biological target do have
a longer duration of action than drug molecules that participate in noncovalent
interactions, it is important to be cautious when championing this property. It
should be no surprise that the effects of covalently bound drugs are not as readily
reversed (if at all!) as those associated with drugs that participate in noncovalent
interactions; however, there is a possibility that the overall duration of drug action
may be too long for the desired therapeutic effect (representing a potential
disadvantage).

As you might expect, the possibility for drug misadventure, as mentioned

previously, represents the major disadvantage associated with drugs that form
covalent bonds with their biological targets. Because the active form of the drug
is highly reactive, the potential for the drug to react with a nearby protein can
be significant. As a result, special preparation and administration guidelines may
need to be in place to ensure that drug activation occurs in close proximity to the
desired biological target.

CHAPTER 7
1. The structure of venetoclax does not contain any chiral centers; however, there
CHAPTERare
7 14 potential prochiral centers. These have been identified below. With the
exception of prochiral center 2, the metabolic addition of a functional group to
STRUCTURE ANALYSIS
any CHECKPOINT
of these carbon atoms would result in a chiral center. For prochiral center 2,
Checkpointthe addition of a functional group to either of the adjacent methyl groups would
Drug 1: Venetoclax
create a chiral center. At this point, we are only looking at potential prochiral
centers.
1. The structure In Chapter 8,
of venetoclax afternot
does wecontain
have discussed all of
any chiral the metabolic
centers; however,pathways,
there are 14
we will revisit this question to see which of these potential prochiral centers can
actually be converted to a chiral center.
11 12
10
6 7
5 13 14
8 9
1 4
2 3
Venetoclax
2. Part A: No. Drug molecules need to have at least one chiral center in order to
have enantiomers. The structure of venetoclax does not contain any chiral centers,
so it is not possible for it to have enantiomers.
Part B: No. Drug molecules need to have at least two chiral centers in order
to have diastereomers. The structure of venetoclax does not contain any chiral
centers, so it is not possible for it to have diastereomers.
Part C: No. Geometric isomers are a specialized type of diastereomers that

occur due to the presence of an alicyclic ring or a double bond. The structure of
venetoclax does contain two alicyclic rings; however, as mentioned above, neither
of these contains a chiral center. The cyclohexene ring that is attached to the para-
chlorophenyl ring does contain a double bond; however, due to the geometry and
rigidity of a six-membered ring, it is not able to have cis and trans isomers. In order
to have geometric isomers, the double bond needs to be in an aliphatic chain and
not a ring.
Part D: Yes. Conformational isomers result from the rotation of single bonds
with a drug molecule. Since the structure of venetoclax contains numerous single
bonds that can undergo free rotation, it is possible for venetoclax to have multiple
conformational isomers.

3. Shown below are three conformational isomers of venetoclax. Although all of these
conformational isomers are possible, conformational isomer 2 requires rotation of
a bond involved in the resonance stabilization of the sulfonamide and may be less
3. Shown
likelybelow
than are
the three
otherconformational
two. isomers of venetoclax. Although all of these
3. Shown below are three conformational isomers of venetoclax.

RotationAlthough
about all of these
single bond
Rotation about
single bond
Conformational Isomer 1
Rotation about
single bond
Conformational Isomer 1 Conformational Isomer 2
Rotation about
single bond
Rotation about
single bond
4. Cyclohexane and other six-membered, nonaromatic, heterocyclic ring systems (i.e., a

4. Cyclohexane and other six-membered, nonaromatic, heterocyclic ring systems (i.e., a
piperazine ring) can adopt either a chair or boat conformation. Of these two options,
Rotation about
chair
singleconformations
bond are preferred due to lower steric hindrance (or repulsion) and
the presence of staggered bonds Conformational Isomer 3 to eclipsed bonds seen in boat
(as compared
..
formations). Similar to chair-chair inversion seen with cyclohexane, the ability of
nitrogen atoms to undergo inversion of their lone-pair of electrons allows for the
minimization of steric hindrance (or .. repulsion) and the maximization of attractive
forces.and
4. Cyclohexane In the case
other of venetoclax,
six-membered, the nitrogenheterocyclic
nonaromatic, atoms in the piperazine
ring ringaare
systems (i.e.,
attached to aromatic and alicyclic rings. Due to steric reasons, these groups should
be oriented such that they both Predicted
occupy equatorial
preferred
positions as shown below.
..
conformation
..
Predicted preferred
conformation

5. The pyrrolopyridine ring can assume a variety of conformational orientations

relative to its adjacent aromatic ring and the meta piperazine ring and the ortho
side chain attached to this ring. The pyrrolopyridine ring can rotate about two
bonds indicated in the structure below. Due to the rigidity and distance of the
piperazine ring, it would not be expected to influence the conformation of the
pyrrolopyridine ring. Rotation about bond A would allow the pyrrolopyridine ring
to lie parallel to the adjacent aromatic ring, perpendicular to the adjacent aromatic
ring, and any intermediate orientation. There are minimal steric factors affecting
this rotation. Rotation about bond B would allow similar orientations; however,
rotations approaching 135–180° would cause increasingly significant steric
5. The pyrrolopyridine ringthe
interactions with canortho
assume
sideachain
variety
andofwould
conformational orientations
not be favored. relative
In terms of bond to its
B, the orientation shown below of the pyrrolopyridine with respect to the ortho
side chain provides the least steric hindrance.

1. ThereCheckpoint Drug
are four chiral 2: Elamipretide
carbons present in elamipretide.
1. There are four chiral carbons present in elamipretide.
Elamipretide

2. For the arginine component of elamipretide, there are three additional prochiral
carbons.
For the tyrosine derivative component of elamipretide, there is one additional
prochiral carbon.
For the lysine component of elamipretide, there are four additional prochiral
carbons.
For the phenylalanine component of elamipretide, there is one additional prochiral
carbon.
3. Part A: Enantiomers must contain at least one chiral carbon. Elamipretide contains
four chiral carbons. In order to produce an enantiomer of elamipretide (SSRS
= configuration as drawn), all of the chiral carbons would need to be in their
opposite configuration (RRSR).
Part B: In order for a molecule to have diastereomers, it must contain at least two
chiral carbons. Elamipretide contains four chiral carbons. In order to produce a
diastereomer of elamipretide (SSRS = configuration as drawn), at least one of the
chiral carbons must be in its opposite configuration (RSRS). There are many, many
diastereomers possible for elamipretide!!!
4. Geometric isomers are not possible for elamipretide because it does not contain a
double bond or alicyclic ring system.
5. Because elamipretide contains numerous rotatable single bonds, not only at

the ends of the molecule but in the middle of the molecule, it is considered
conformationally flexible. In addition, it does not contain any double bonds or
rigid ring systems.

ZĞƉůĂĐĞŵĞŶƚĨŽƌƉƉĞŶĚŝǆ͕ƉĂŐĞϰϬ;ŶƐǁĞƌĨŽƌYϭͿ
REVIEW QUESTIONS
1. Chiral carbon atoms are identified below with asterisks. Circled carbon atoms are
identified below as being prochiral or not prochiral.
2
%
+ & 2 &
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2. Priority #1: substituted amine
Priority #2: CH2-halogenated aromatic hydrocarbon
Priority #3: methyl group
Priority #4: hydrogen atom
The R enantiomer is drawn.
3. Similar properties: molecular weight, infrared (IR) and nuclear magnetic resonance
(NMR) spectral properties, log P values, water/lipid solubility balance, dissolution
rates, pKa values of the amine group, and the percent ionization at any given pH
value.
Different property: direction that the molecule rotates plane polarized light.

REVIEW
4. QUESTIONS
Correct matches are shown below.
1. Chiral carbon atoms are identified below with asterisks. Circled carbon atoms are
(+)/(-) matches with Direction that enantiomer rotates plane polarized light
Dextrorotatory/levorotatory
d/l matches with Direction that enantiomer rotates plane polarized light
Dextrorotatory/levorotatory
D/L matches with Absolute configuration
Steric arrangement of atoms about a chiral carbon
R/S matches with Absolute configuration
Steric arrangement of atoms about a chiral carbon
5. Part A: Only one (+)/(-) designation that indicates the net rotation of plane
polarized light.
Part B: Yes, it can have an enantiomer (non-superimposable mirror image), a

diastereomer (non-superimposable non-mirror image), and conformational isomers
(non-superimposable isomers that differ due to free rotation of atoms about single
bonds). There is not enough information provided to determine if a geometric
isomer is possible (e.g., no information related to presence of rings or double
bonds).
6. The R enantiomer is drawn. It is possible that the two biological targets (reuptake
transporters) have stereochemical differences for their interaction requirements.
For example, in the R enantiomer the aromatic ring is pointed behind the plane
of the paper where there is a suitably large hydrophobic pocket present in the
serotonin-related biological target. In the S enantiomer, this aromatic ring is
pointed in front of the plane of the paper (opposite side as R enantiomer), where
there may be a suitably large hydrophobic pocket present in the norepinephrine-
related biological target.
7. Chiral centers have been circled below.
7. Chiral centers have been circled below.
H H
H 3C N H3 C N
OCH3 OCH3
Similarities to enantiomers: Same molecular formula, not superimposable

Differences from enantiomers: Not mirror images, different chemical and physical properties may have
different pharmacological activities.
At least one of the stereocenters has not changed configuration between the two
structures; therefore, these two isomers are diastereomers.

8. Priority of the double bond substituents using the CIP system are listed below.
Priority #1: Ether side chain with primary amine

Priority #2: Nonbonding electrons on nitrogen atom
Priority #1′: Substituted aromatic hydrocarbon
Priority #2′: Methyl ether side chain
Because the two #1 priorities are on opposite sides of the double bond, therefore
the structure above is drawn as the trans (E) isomer.
9. Tranexamic acid is a conformationally restricted analog of aminocaproic acid. The

primary amine and the carboxylic acid are both located in equatorial positions, but
on opposite sides of the cyclohexyl ring. The equatorial position is favored in order
to avoid 1,3 diaxial effects. The two substituents on the cyclohexyl ring are trans to
one another (opposite sides of the ring).
The cyclohexyl ring system is a conformationally restricted isomer of the very

flexible aminocaproic acid. The value of this restriction is that the two substituents
(primary amine and carboxylic acid) are now fixed in a particular location in
space relative to one another. This allows for improved interactions with the
lysine receptor (requires less binding energy) and a decrease in the likelihood
of misadventures with other biological targets (increase in specificity for desired
biological target, decrease in adverse events).
10. The 5α-androstane steroid is flatter in shape than the 5β-androstane. In the 5α
isomer, the circled hydrogen atom and the methyl group (bold) are oriented trans
to one another (located on opposite sides of the fused ring system). This permits
the fused cyclohexane rings to remain elongated or flattened in shape. In the 5β
isomer, the circled hydrogen atom and the methyl group (bold) are oriented cis to
one another (located on the same side of the ring system). In this case, the steroid
rings adopt a cupped shape. The mineralocorticoid receptor interacts best with
receptor agonists that are flatter in shape, and it is expected that the 5α isomer
would be the best “fit” for this receptor.

CHAPTER 8
1. Shown below is the answer provided in Chapter 7. Of the 14 potential prochiral
centers, only four of these (1–4) are valid. Carbon atoms 1 and 4 are allylic carbon
atoms and can undergo allylic oxidation that would make these carbon atoms
chiral. Either one of the methyl groups attached to carbon atom 2 can undergo
ω oxidation, thus making carbon atom 2 chiral. Alicyclic rings can be oxidized at
C3 and C4 positions. Carbon atom 3 resides at either the C3 position relative to
carbon atom 5 or the C4 position relative to the para-chlorophenyl ring. Oxidation
of this carbon atom would create a chiral center; however, the probability of this
CHAPTER 8metabolic transformation is decreased due to steric hindrance by the adjacent
dimethyl substitution. Oxidation at carbon atoms 5–10 can occur during the
process of oxidative N-dealkylation. While the initial oxidation of these carbon
atoms produces a chiral center, the resulting carbinolamine is unstable and readily
Checkpoint Drugforms1:anVenetoclax
aldehyde. The same is true with carbon atoms 12 and 14 as they can
be involved with oxidative O-dealkylation. Oxidation at carbon atoms 11 and 13
1. Shown below is highly
is the unlikely. As mentioned
answer provided above, alicyclic
in Chapter 7. Of therings
14 can be oxidized,
potential but centers,
prochiral this
normally occurs at the C3 and C4 positions of a cyclohexane ring and not at the
carbon atoms adjacent to the aliphatic chain.
11 12
10
6 7
5 13 14
8 9
1 4
2 3
Venetoclax
2. Metabolic Pathway A: No. Benzylic oxidation is a Phase I metabolic

transformation that requires an aliphatic carbon atom that is directly attached to an
Metabolic Pathway B: Yes.
aromatic ring. Sulfate
While conjugation
the structure is a Phase
of venetoclax II metabolic
contains transformation.
four aromatic rings, only
two of these are directly attached to an aliphatic carbon. Neither
Sulfate conjugation can occur with aromatic amines. The structure of venetoclaxof these aliphatic
contains
carbon atoms have a hydrogen atom attached and thus cannot be oxidized
two aromatic amines.
Metabolic Pathway B: Yes. Sulfate conjugation is a Phase II metabolic
transformation. Sulfate conjugation can occur with aromatic amines. The structure
of venetoclax contains two aromatic amines.
Sulfate conjugation
could also occur here

two aromatic amines.
Sulfate conjugation
could also occur here
Metabolic Pathway C: Yes. Oxidative N-dealkylation is a Phase I metabolic

Metabolic Pathway
PathwayC:C: Yes.
Metabolictransformation. Oxidative
Yes.AsOxidative
discussedN- dealkylation
N-in Question 1, metabolic
a Phase I metabolic
is venetoclax transformation.
transformation.
has six possible oxidative
N-dealkylation sites. The metabolite shown below results from oxidation at the
least sterically hindered (or most accessible) site.
Metabolic Pathway D: Yes. Glucuronic conjugation is a Phase II metabolic

transformation. Glucuronide conjugation can occur with the sulfonamide (shown),
Metabolicthe
Metabolic Pathway
Pathway D:amine,
D:
tertiary Yes. Glucuronic
Yes. Glucuronic conjugation
conjugation
and the two aromatic is a Phase
is a
amines. It IIII
Phase metabolic
metabolic
should transformation.
transformation.
be noted that due
to steric hindrance and the electron withdrawing properties of the nitro group,
glucuronide conjugation of venetoclax is a minor metabolic pathway.

Metabolic Pathway E: Yes. Hydrolysis is a Phase I metabolic transformation. The bond

Metabolic Pathway E: Yes. Hydrolysis is a Phase I metabolic transformation. The
bond between the benzyl carbonyl and the sulfonamide can be hydrolyzed.
Cl
O O
H 2N S N
O– H
N N O
NO2
O
O
N Venetoclax
N
H
Metabolic Pathway F: No. Alkene oxidation is a Phase I metabolic transformation

that can occur with nonaromatic carbon-carbon double bonds. Although the
structure of venetoclax contains a double bond in the cyclohexene ring, neither
Checkpoint Drug
carbon2:atom
Elamipretide
involved in this double bond bears a hydrogen atom. Thus, this
metabolism cannot occur.
REVIEW QUESTIONS
1. Part C: The pairs of structures drawn below represent the products of oxidative O-
3. All three of these phenyl rings are either electronically deactivated and/or sterically
dealkylation. For this
hindered, particular
thus ether,
minimizing theoxidative O-dealkylation
probability can
that they would occur on
undergo either side of
aromatic
oxidation. The para-chloro phenyl ring is very accessible to metabolism; however,
the oxygen atom.
the electron withdrawing chloro group deactivates the ring. The aromatic ring
in the middle of the molecule is attached to both electron withdrawing groups
(the carbonyl) and electron donating groups (the ether oxygen and the aromatic
amine); however, due to its position in the molecule and the size of the rings and
chains to which it is attached, it is not very accessible to metabolizing enzymes.
It is thus highly unlikely that aromatic oxidation would occur here at this aromatic
ring. Similarly, the aromatic ring with the nitro group is highly sterically hindered
and not very accessible. Additionally, the nitro group is a very strong electron
withdrawing group and will electronically deactivate the ring from aromatic
oxidation.
4. There are two sites of metabolic transformation, the nitro group and the
tetrahydropyran ring (i.e., the oxygen containing alicylic ring). The nitro group
is first reduced to a primary aromatic amine. This is followed by acetylation. The
tetrahydropyran ring first undergoes oxidative O-dealkylation to give a primary
hydroxyl group and an aldehyde. The aldehyde is further oxidized by ALDH
enzymes to a carboxylic acid. The carboxylic acid then undergoes amino acid
conjugation to yield the final metabolic product.


1. The cLogP for elamipretide is 0.3677 which indicates significant water solubility
(the amount of hydrophilic character of guanidine, primary amines, phenol, and
multiple amides is greater than the hydrophobic character of phenol, aromatic
hydrocarbon). The ability of the guanidine and two primary amines to be
predominantly ionized in most physiological environments contributes to the
overall water solubility of elamipretide. Because renal elimination requires a drug
to be highly water soluble, it is likely that elamipretide can be eliminated without
the need for Phase I or Phase II metabolic transformation.
2. No, a Phase I transformation does not need to occur prior to a Phase II

transformation. The primary amine can directly undergo a Phase II acetylation
transformation. The phenol can directly undergo a phase II POMT catalyzed
O-methylation, as well as Phase II sulfation and glucuronidation transformations.
3. Primary amine (amino terminus): oxidative deamination; N-oxidation

Primary amine (lysine): oxidative deamination; N-oxidation
Phenol: benzylic oxidation of CH3; benzylic oxidation of CH2 (prochiral carbon);
aromatic hydroxylation (ortho, para)
Aromatic hydrocarbon: benzylic oxidation of CH2 (prochiral carbon); aromatic
hydroxylation (ortho, para)
Amide: amide hydrolysis
4. This prodrug must undergo the following metabolic transformations to become

the active drug:
Primary amine (amino terminus): amide hydrolysis
Phenol: oxidative-O-dealkylation
REVIEW QUESTIONS
1. Part A: Para and ortho aromatic hydroxylation; oxidative O-dealkylation;
N-oxidation (imidazole, minor pathway).
Part B: The typical products of S-dealkylation are either a thiol and an aldehyde
or a thiol and a ketone. In fenticonazole, the sulfur atom is bound to carbon atoms
that are components of aromatic hydrocarbons. These carbons do not have a
hydrogen atom attached to them and therefore cannot undergo oxidation to form
a ketone.

$QVZHU

Part C: The pairs of structures drawn below represent the products of oxidative
&7KHSDLUVRIVWUXFWXUHVGUDZQEHORZUHSUHVHQWWKHSURGXFWVRIR[LGDWLYH2GHDON\ODWLRQ)RU
$QVZHU O-dealkylation. For this particular ether, oxidative O-dealkylation can occur on
either side of the oxygen atom.
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1
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Part D: First, consider the answers you provided for possible Phase I metabolic
.HWRQH
transformations; then, 3KHQRO
determine how you could modify of
the structure
fenticonazole to prevent para and/or ortho aromatic hydroxylation or oxidative
')LUVWFRQVLGHUWKHDQVZHUV\RXSURYLGHGIRUSRVVLEOHSKDVH,PHWDEROLFWUDQVIRUPDWLRQVDQGWKHQ
O-dealkylation.
The addition of fluoro substituents in the ortho and para positions (several
$GGLWLRQRIIOXRURVXEVWLWXHQWVLQWKHRUWKRDQGSDUDSRVLWLRQVVHYHUDOH[DPSOHVEXWQRWDOO
examples, but not all possibilities are shown below) can limit Phase I metabolic
')LUVWFRQVLGHUWKHDQVZHUV\RXSURYLGHGIRUSRVVLEOHSKDVH,PHWDEROLFWUDQVIRUPDWLRQVDQGWKHQ
transformation of this molecule into a more water-soluble analog (that is easily
eliminated). Fluoro substituents are electron withdrawing in character and will
1
deactivate the aromatic ring toward metabolic aromatic hydroxylation similar to
$GGLWLRQRIIOXRURVXEVWLWXHQWVLQWKHRUWKRDQGSDUDSRVLWLRQVVHYHUDOH[DPSOHVEXWQRWDOO
that observed with the chloro
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Replacement of the ether oxygen with a methylene (CH2) group will prevent Phase
5HSODFHPHQWRIWKHHWKHUR[\JHQZLWKDPHWK\OHQH&+ JURXSZLOOSUHYHQWSKDVH,PHWDEROLF
I metabolic transformation (oxidative O-dealkylation) of this molecule into a more
water-soluble analog (that is easily eliminated). JURXSZLOOSUHYHQWSKDVH,PHWDEROLF
5HSODFHPHQWRIWKHHWKHUR[\JHQZLWKDPHWK\OHQH&+

2. The typical products of oxidative O-dealkylation are either an alcohol and an aldehyde
&RQVLGHUWKHVWUXFWXUHEHORZDQGGRWKHIROORZLQJ
&RQVLGHUWKHVWUXFWXUHEHORZDQGGRWKHIROORZLQJ
or an alcohol and a ketone. Like we saw with the thioether in fenticonazole, the
oxygen atom of the ether functional group that is crossed out is bound to carbon
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hydrogen atom attached to them and therefore cannot undergo oxidation.
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3. All possible Phase I metabolic transformations are provided below.
'LDSODVLQLQLVDQLQYHVWLJDWLRQDOILEULQRO\WLFDJHQWLQFOLQLFDOWULDOV/LVWDOORIWKHSRVVLEOH$QVZHU
3. All possible Phase I metabolic transformations are provided below.
'LDSODVLQLQLVDQLQYHVWLJDWLRQDOILEULQRO\WLFDJHQWLQFOLQLFDOWULDOV/LVWDOORIWKHSRVVLEOH$QVZHU
Oxidative
R[LGDWLYH deamination
R[LGDWLYH
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hydrolysis
NH H S-dealkylation
SDUDDURPDWLF 2+ 2
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K\GUR[\ODWLRQ 1 1DPHVRI7UDQVIRUPDWLRQV
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R[LGDWLRQ
Oxidative deamination SURGXFWVQRWVKRZQ
2[LGDWLYH2GHDON\ODWLRQ
4. There areAmide
two aromatic rings
hydrolysis in the molecule and potentially two benzylic carbons (see
SURGXFWVQRWVKRZQ
S-dealkylation
Epoxidation/peroxidation
Allylic oxidation

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3DJHRI
&RQVLGHUWKHVWUXFWXUHRIHPEHFRQD]ROHGUDZQEHORZ&DQHPEHFRQD]ROHXQGHUJREHQ]\OLF
4. There are two aromatic rings in the molecule and potentially two benzylic carbons
(see arrows). One benzylic carbon already has a hydroxyl substituent, and the other
$QVZHU
is part of a double bond. Neither can undergo benzylic oxidation as neither carbon
bears a requisite hydrogen atom.
)
2+
6 1
) 2 1
& + 1
2
+
1&
(PEHFRQD]ROH

5. Amide: Amide hydrolysis (Phase I) followed by acetylation (Phase II)
&RQVLGHUWKHVWUXFWXUHRIDUIRUPRWHUROGUDZQEHORZ/LVWDOORIWKHSRVVLEOHSKDVH,
Ether: Oxidative O-dealkylation (Phase I) followed by sulfation (Phase II)
Secondary alcohol: Alcohol oxidation (Phase I)
Phenol: Aromatic hydroxylation (ortho, para) (Phase I)
2+ +
6. Possible Phase I metabolic transformations of metoprolol are listed and shown
1
below:
Alcohol oxidation & +
+2
Benzylic oxidation 2&+
1 +
Oxidative O-dealkylation (methyl ether and phenyl ether)
+
Oxidative N-dealkylation
2
ω/ω-1 oxidation $UIRUPRWHURO
Aromatic hydroxylation (ortho)
3DJHRI

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$QVZHU APPENDIX: ANSWERS TO CHAPTER QUESTIONS 547
2&+ 2&+
6. Possible Phase I metabolic transformations of metoprolol are listed and shown below:
2 + 2+ +
2 1 & + 2 1 & +
+
& + + & 2
2&+
2[LGDWLYH
$OFRKROR[LGDWLRQ 1GHDON\ODWLRQ
+2
2+ 2&+ 2&+
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2 & +
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7. Lists of all Phase I and Phase II metabolic transformation for each drug are provided below.
7. Lists of all Phase I and Phase II metabolic transformation for each drug are
provided below.
O
3DJHRI
HO
OH
OH
HO
H
HO N
F
C H3
HO O
Dobutamine Fludrocortisone
Dobutamine Fludrocortisone
Aromatic hydroxylation (ortho, para) Allylic oxidation
Oxidative N-dealkylation Alcohol oxidation (secondary)
Benzylic oxidation Reduction
Phase II: COMT catalyzed O-methylation; POMT Phase II: Glucuronidation
catalyzed O-methylation; sulfation; glucuronidation

POMT catalyzed O-methylation; Sulfation;
glucuronidation
Hydroxyzine Isalmodol
Aromatic hydroxylation (ortho, para) Aromatic hydroxylation (ortho, para)
Isalmadol
Oxidative N-dealkylation Ester hydrolysis
Hydroxyzine
N-oxidation Oxidative N-dealkylation
Oxidative
Hydroxyzine O-dealkylation Isalmodol N-oxidation
Aromatic hydroxylation (ortho, para) Aromatic hydroxylation (ortho, para)
Alcohol oxidation Phase II: POMT catalyzed O-methylation
Oxidative N-dealkylation Ester hydrolysis
N-oxidation sulfation;
Oxidative N-dealkylation glucuronidation
Oxidative O-dealkylation N-oxidation
Phase II: Glucuronidation
Alcohol oxidation Phase II: POMT catalyzed O-methylation; sulfation;
glucuronidation
Phase II: Glucuronidation
Pravastatin Lisinopril
Pravastatin Lisinopril
ω/ω-1 oxidation Aromatic hydroxylation (ortho, para)
Ester hydrolysis Benzylic oxidation
Allylic oxidation Amide hydrolysis
Epoxidation/peroxidation Oxidative deamination
Alcohol oxidation Oxidative N-dealkylation
Phase II: Amino acid conjugation; glucuronidation Phase II: Acetylation; glucuronidation; amino acid
conjugation

Tolvaptan
Tolvaptan
ω/ω-1 oxidation Tolvaptan
Benzylic oxidation (of 1,3-oxazole)
Z/Z-1 oxidation
)RUHDFKRIWKHGUXJPROHFXOHVGUDZQEHORZGHWHUPLQHZKLFKRIWKHIROORZLQJLV758(
Aromatic hydroxylation (ortho, para)
Phase Benzylic oxidation
II: only after Phase I transformation (of 1,3-oxazole)
)RUHDFKRIWKHGUXJPROHFXOHVGUDZQEHORZGHWHUPLQHZKLFKRIWKHIROORZLQJLV758(
(e.g., sulfation)
$QVZHU
$QVZHU
8. Answers for eachPhase
drug molecule are shown
II: only after Phasebelow.
I transformation & +
& +&2
+
(e.g., sulfation)
+& &2 +
+& & +

& +
5LYDVWLJPLQH ,EXSURIHQ
5LYDVWLJPLQH ,EXSURIHQ

(B) = True (A) Glucuronidation; amino acid

% 7UXH $*OXFXURQLGDWLRQDPLQRDFLGFRQMXJDWLRQ
conjugation
% 7UXH $*OXFXURQLGDWLRQDPLQRDFLGFRQMXJDWLRQ
2
) &2 +
2
2 ) &2 +
+2 1 1
1
2
+2 +1
1 1
1
) +1
&LSURIOR[DFLQ
)
+DORSHULGRO
+DORSHULGRO &LSURIOR[DFLQ
(B) = True; Tertiary alcohol too sterically hindered (A) Glucuronidation; amino acid
to undergo glucuronidation to conjugation
conjugation


H3HC C NN
3
NN
Cl
Cl NN
OOHH
O
O NH
NH22 ClCl NN
NN
Loperamide
Loperamide Alprazolam
Alprazolam
(B)
(B) =
= True;
True; Tertiary
Tertiary alcohol
alcoholtoo
toosterically
stericallyhindered
hindered (B)(B)= =True
True
(B) = True; Tertiary alcohol too sterically hindered (B) = True
to undergo glucuronidation
H2 N
H2 N
O C H3 N
O N C H3 N
N
O H S Cl
O H S Cl
Procainamide Ticlopidine
Procainamide Ticlopidine
(A)(A)Glucuronidation;
Glucuronidation; acetylation
acetylation (B) = True
(B) = True
(A) Glucuronidation; acetylation (B) = True
Trimetrexate Repaglinide
(A) Glucuronidation (secondary amine) (A) Glucuronidation amino acid conjugation
Trimetrexate Repaglinide
(A)(A)Glucuronidation
Glucuronidation (secondary amine)
(aniline nitrogen) (A) Glucuronidation
(A) Glucuronidation;amino acidacid
amino conjugation

conjugation
Flesinoxan
Zolmitriptan
Flesinoxan
(A) Glucuronidation of primary OH (B) = True
(A) Glucuronidation of primary alcohol (B) = True
Zolmitriptan
(A) Glucuronidation of primary OH (B) = True
$QVZHU
9. Phase I and Phase II metabolic transformations for celivaronum are identified
below.
+ &
& +
2
1 & +
2
262 & +
2
+ &

Aromatic hydroxylation (ortho) (Phase I)

$URPDWLFK\GUR[\ODWLRQRUWKRSKDVH,
Sulfate conjugation (Phase II)
6XOIDWHFRQMXJDWLRQSKDVH,,
+ &
& +
2
1 & +
2*OXF
2
& +
2
+ &

Omega-1 oxidation (Phase I)
2PHJDR[LGDWLRQSKDVH,
Glucuronic acid conjugation (Phase II)
*OXFXURQLFDFLGFRQMXJDWLRQSKDVH,,
Oxidative N-dealkylation (Phase I) 3DJHRI

2[LGDWLYH1GHDON\ODWLRQSKDVH,
Oxidative N-dealkylation (Phase I)
2[LGDWLYH1GHDON\ODWLRQSKDVH,
Acetylation (Phase II)

$FHW\ODWLRQSKDVH,,

CHAPTER 9
1. The alteration of functional groups on the aromatic ring can change the solubility
of the drug molecule, the electronics of the aromatic ring, and/or the overall
steric size of the aromatic ring and drug molecule. In examining the six functional
groups and the activity profile, the difference in steric size does not explain the
activity profile. The NO2 and CN groups enhanced activity, while the OCH3, a
functional group of similar size, caused an elimination of activity. The same is
true with solubility. While the OH and OCH3 groups are more water soluble than
the original chloro group, the CH3 has similar solubility to the chloro group.
All three of these functional groups caused either a decrease or elimination of
activity. Thus, the changes in activity must be due to the electronic differences
in the functional group. The original Cl group is electron withdrawing due to
induction. Replacement with functional groups that are electron withdrawing
due to induction—the F group—retain activity, while replacement with functional
groups that are electron withdrawing through resonance—the NO2 or CN groups—
enhance activity. As discussed in Chapter 2, the ability to donate or withdraw
electrons through resonance is stronger than the ability to donate or withdraw
electrons through induction. The CH3, OH, and OCH3 all decrease or eliminate
activity. All of these functional groups are electron donating, the CH3 through
induction, and the OH and OCH3 through resonance. Given all of this information,
the following SAR statements can be made:
• Electron withdrawing functional groups on this aromatic ring enhance activity,
while electron donating groups detract from activity.
• Those functional groups that withdraw electrons through resonance enhance
the activity to a greater extent than those that can only withdraw electrons
through induction.
• Functional groups that can donate electrons through resonance eliminate
activity.
2. The original pyrrolopyrimidine bicyclic ring can interact with its biological target
through hydrogen bonds, van der Waals interactions, π-π stacking, and cation-π
interactions. In evaluating these four analogs, the major difference among them is
their ability to form specific types of hydrogen bonds. The pyrrole nitrogen (i.e.,
the one in the five-membered ring) acts as a hydrogen bond donor, while the
pyrimidine nitrogen (i.e., the one in the six-membered ring) acts as a hydrogen
bond acceptor. The only analog to retain activity is Analog B. This bicyclic indole
ring retains the nitrogen atom that can act as a hydrogen bond donor. Please
note that the location/position of the hydrogen bond donor is the same. Analog
D also has a nitrogen atom that can act as a hydrogen bond donor; however, due
to the fact that the pyrrolopyrimidine is now attached to the rest of the molecule
via a different carbon atom, this hydrogen bond donor is located or positioned
differently. As such, the strength of the hydrogen bond to the biological target

is not as strong leading to the 10-fold loss in activity. Analogs A and C lack a
hydrogen bond donor in the aromatic ring and are thus inactive. Given this
information, the following SAR statement can be made:
• The pyrrolopyridine ring provides a key hydrogen bond (as the donor) to its
biological target. This bicyclic ring can be altered as long as the position of the
hydrogen bond donor is unaltered.
3. Replacing the ether oxygen atom with a secondary amine will enhance the water
solubility of venetoclax. The ether oxygen atom can form hydrogen bonds with
water (as the acceptor); however, the secondary amine will be primarily ionized at
physiological pH and thus be able to form ion-dipole interactions with water (as
the ion). An ion-dipole bond enhances water solubility to greater extent than a
hydrogen bond. Additionally, the presence of an ionized amine would allow this
isostere of venetoclax to participate in ionic or ion-dipole bonds with its biological
target. This is assuming that complementary functional groups are present on the
biological target. The presence of an ionized amine could also cause a decrease in
the overall binding activity. The tetrahydropyran ring may reside in a hydrophobic
pocket with the most important interactions occurring via van der Waals
interactions with the carbon atoms. If this is true, then the presence of an ionized
secondary amine may decrease drug binding and activity. Given that “O” and
“NH” are pseudoatoms and classical isosteres, it would be expected that these
groups would be similar in size and thus not alter activity due to steric reasons. The
same is true for the methylene carbon.
Replacing the ether oxygen with a methylene group will decrease water solubility
and increase lipid solubility of the drug. As mentioned above, the ether oxygen
atom can form hydrogen bonds with water, while the methylene group cannot. In
terms of receptor binding, if the ether oxygen was essential in forming a hydrogen
bond (as the acceptor) with its biological target, then this isosteric substitution
could decrease the activity of this analog. Conversely, if the tetrahydropyran ring
resides in a hydrophobic pocket, this isosteric replacement could enhance van der
Waals interactions with its biological target.
4. The answer is “NO” with the key word being “easily.” The easiest way to convert
a drug molecule to a more water- or lipid-soluble prodrug is to form an ester as
these functional groups can be easily hydrolyzed back to the active drug at various
locations within the body. In order to form an ester, the structure of the drug must
contain either a carboxylic acid or a hydroxyl group that is easily accessible to
esterase enzymes. Because neither of these functional groups is present within
the structure of venetoclax, it cannot be easily converted to a prodrug. For the
sake of completeness, it should be noted that it is theoretically possible to make
a prodrug from the sulfonamide functional group; however, this would create a
sterically hindered site that may be difficult to access by metabolizing/activating
enzymes.


1. Possible binding interactions are provided in the table below.
Amino Terminus Carboxy Terminus

SS-31 (elamipretide) Ionic Cation-π
Ion dipole π-π stacking
Cation-π Hydrophobic
Chelation H-bonding
Ion-dipole (dipole)
SS-02 Ionic Ionic
Ion-dipole (ion) Ion-dipole (ion)
Ion-dipole (dipole) Ion-dipole (dipole)
Cation-π H-bonding
H-bonding Cation-π
π-π stacking Chelation
Hydrophobic
SS-20 Ionic Ionic
Ion-dipole (ion) Ion-dipole (ion)
Cation-π Ion-dipole (dipole)
π-π stacking H-bonding
Hydrophobic Cation-π
Chelation
SS-02 is the only analog that can participate in H-bonding and ion-dipole (as the
dipole) at the amino terminus (via the phenol OH) at physiological pH. These types
of interactions might be important for µ receptor activation.
2. At physiological pH the basic functional groups (guanidine and primary amine)

found within elamipretide and the two analogs will be ionized and able to
interaction via an ionic interaction with a phosphate head. In all three molecules,
the two amino acids with basic side chains are always separated by one amino acid
and are therefore always in the same proximity to one another.
3. In elamipretide and in SS-20, the tyrosine derivative is located between the amino
acids with the basic side chains. In SS-02 the phenylalanine residue is located
between the amino acids with the basic side chains. The basic side chains are
required for an important electrostatic interaction with the phosphate head found
within cardiolipin. It is possible that cardiolipin also requires a particular type of
interaction (ion-dipole, H-bonding, or dipole-dipole) between these two basic
amino acids for optimal binding. If this is the case, then SS-02 would not have the
right type of functionality to participate in this important interaction (ion-dipole,
H-bonding, or dipole-dipole) with cardiolipin.

4. Part A: There are several reasons why a lipophilic ester prodrug might be valuable
including improving bioavailability and the related absorption across lipophilic
membranes. Prodrugs also protect drug molecules from metabolic and/or
enzymatic degradation, as well as may prevent metabolic transformations that lead
to rapid drug elimination.
Part B: This prodrug form of elamipretide contains amides at both the amino-
and carboxy terminus. Amino- and carboxypeptidases require their substrates
to contain either a primary amine or carboxylic acid (respectively). In order to
fool these enzymes, these functional groups can be “protected” or “masked” as
amides. Once the primary amine and/or carboxylic acid is modified to be an amide
(prodrug), then the amino- and carboxypeptidases no longer recognize the drug
as a substrate, thus extending the half-life of the drug. Since amides are relatively
easily cleaved to the corresponding carboxylic acid and amine (Phase I metabolic
transformation catalyzed by amidases), they serve as valuable prodrugs.
REVIEW QUESTIONS
1. Part A, Insulin #1: Inactive—three disulfide bonds must be present to allow insulin
to adopt the correct conformation. In this scenario the amino and carboxy terminal
amino acid residues are identical to that found in endogenous insulin; however, if
the amino acids at the amino or carboxy termini of the A chain are different than
that found in the endogenous hormone, then the key receptor interactions may
not occur and the corresponding analog would be biologically inactive.
Part B, Insulin #2: Inactive—only six amino acids can be removed from the amino
terminus of the B chain and still retain biological activity. In this case 10 amino
acids are missing from the amino terminus of the B chain.
Part C, Insulin #3: Inactive—there is a good chance that this insulin analog
will be inactive due to the number of D-amino acids present. The change in
stereochemistry in so many locations will more than likely not only change the
shape of the insulin molecule (amino acid side chains may not be located in the
right place in space to allow for the appropriate secondary and ternary structural
features to form), but also may influence how many amino acids can interact with
the insulin receptor.
2. Glipizide contains an acidic sulfonylurea functional group, whereas repaglinide

contains an acidic carboxylic acid functional group. This molecular modification
is an example of the use of a non-classical bioisostere. There are several other
molecular modifications that you might have identified, including shortening the
hydrocarbon chain between the arylsulfonylurea and the amide functional groups,
reversal of the placement of the amide carbonyl group, and replacement of an
aromatic heterocycle with an aromatic hydrocarbon.

3. Insulin lispro contains a proline residue as part of its primary structure; however, it
is in closer proximity to the carboxy terminus as a result of a structural exchange
of the Lys29 with the Pro28. You might imagine that the size of the “hook” is
now smaller (only one amino acid in length) and that the likelihood of insulin
dimerization will decrease. This is in fact exactly what happens!!! As a result of this
structural modification there is more monomer present in the formulation and the
time that it takes for the insulin dimer present to dissociate into two monomers is
likely to be shorter than that required for Humulin R.
Insulin aspart does not contain a proline residue as part of its primary structure.
This means that there is no “hook” present within the carboxy terminus of the B
chain of this insulin analog. This means that this analog will not dimerize and will
only need to dissociate from the insulin stabilizer present in the formation (which
is true for all insulin formulations) in order to be an active drug. This will take less
time and, therefore, the onset and duration of action is shorter than Humulin R.
Note: Although insulin glulisine is also considered an ultra-short acting insulin, the
rationale for this has nothing to do with the primary structure (Pro28 is present), but
rather has to do with the type of insulin stabilizer used in the formulation.
4. Tazarotene is formulated as a topical agent in the treatment of several skin

disorders. For this drug to penetrate the affected skin, it must be highly
hydrophobic in character. Although the carboxylic acid is important for biological
activity, it is very hydrophilic and limits the ability of the drug to be appropriately
formulated for topical use. Formation of the ethyl ester significantly decreases the
hydrophilic character of this functional group and, therefore, not only improves the
overall characteristics from a formulation perspective, but also improves the ability
of the drug to penetrate the skin.
5. For many years ciprofloxacin represented the gold standard to which other
fluoroquinolones were compared. Thousands of analogs were synthesized,
with only a handful exhibiting equal or better action against gram-negative
pathogens. When looking at the analog series A–D, there is a progressive
addition of hydrocarbon character associated with the N atom substituent. Once
this substituent contains more than three carbons, there is a complete loss of
biological activity. One could surmise that the interaction between the drug and its
biological target allows for a finite amount of hydrophobicity/bulk in this location,
and once this hydrophobic space is exceeded, the interaction of the drug with the
biological target suffers significantly.

ŐĞƐϱϵͲϲϭŝŶĐƵƌƌĞŶƚW&Ϳ
ŶĚƚŚĞƐƚƌƵĐƚƵƌĞŽĨZͲϭϵϬϭĂƌĞĨŝŶĞ͘tŚĂƚĨŽůůŽǁƐŝƐĂƌĞĨŽƌŵĂƚƚŝŶŐŽĨƚŚĞĂŶƐǁĞƌ͘
ϲ;ƉĂŐĞƐϱϵͲϲϭŝŶĐƵƌƌĞŶƚW&Ϳ
ƐƚƌƵĐƚƵƌĞƐŶĞĞĚƚŽďĞƉůĂĐĞĚǁŝƚŚƚŚĞĂƉƉƌŽƉƌŝĂƚĞĂŶƐǁĞƌ;ĂŶĚŶŽƚĂůůĂƚƚŚĞĞŶĚͿ͘
6. Analog A: Replace phenol OH with F.
ŝŽŶĂŶĚƚŚĞƐƚƌƵĐƚƵƌĞŽĨZͲϭϵϬϭĂƌĞĨŝŶĞ͘tŚĂƚĨŽůůŽǁƐŝƐĂƌĞĨŽƌŵĂƚƚŝŶŐŽĨƚŚĞĂŶƐǁĞƌ͘
This decreases the potential for Phase I catechol formation and Phase II sulfation,
ƚŚĞƐƚƌƵĐƚƵƌĞƐŶĞĞĚƚŽďĞƉůĂĐĞĚǁŝƚŚƚŚĞĂƉƉƌŽƉƌŝĂƚĞĂŶƐǁĞƌ;ĂŶĚŶŽƚĂůůĂƚƚŚĞĞŶĚͿ͘
glucuronidation, and O-methylation catalyzed by POMT.
+
ĂĐĞƉŚĞŶŽůK,ǁŝƚŚ&͘
+ & 1
ƚŚĞƉŽƚĞŶƚŝĂůĨŽƌWŚĂƐĞ/ĐĂƚĞĐŚŽů +
ZĞƉůĂĐĞƉŚĞŶŽůK,ǁŝƚŚ&͘
+ & 1
WŚĂƐĞ//ƐƵůĨĂƚŝŽŶ͕ŐůƵĐƵƌŽŶŝĚĂƚŝŽŶ͕ĂŶĚ +& 1 2&+
ĂƐĞƐƚŚĞƉŽƚĞŶƚŝĂůĨŽƌWŚĂƐĞ/ĐĂƚĞĐŚŽů
ĂWKDd͘
ĂŶĚWŚĂƐĞ//ƐƵůĨĂƚŝŽŶ͕ŐůƵĐƵƌŽŶŝĚĂƚŝŽŶ͕ĂŶĚ +& 1 2&+

ŽŶǀŝĂWKDd͘ )
$QDORJ$

)

Analog B: Replace oxygen atom in methyl ether substituent with a methylene unit
$QDORJ$
(CH2).

This decreases the potential for Phase I oxidative O-dealkylation (potentially
ĂĐĞŽǆǇŐĞŶĂƚŽŵŝŶŵĞƚŚǇůĞƚŚĞƌ +
followed by Phase II sulfation, glucuronidation, and O-methylation catalyzed by
POMT). +& 1
ƚŚĂŵĞƚŚǇůĞŶĞƵŶŝƚ;,ϮͿ͘
ZĞƉůĂĐĞŽǆǇŐĞŶĂƚŽŵŝŶŵĞƚŚǇůĞƚŚĞƌ +
ƚŚĞƉŽƚĞŶƚŝĂůĨŽƌWŚĂƐĞ/ŽǆŝĚĂƚŝǀĞKͲ +& 1
ŶƚǁŝƚŚĂŵĞƚŚǇůĞŶĞƵŶŝƚ;,ϮͿ͘
+& 1 &+ &+
ŽƚĞŶƚŝĂůůǇĨŽůůŽǁĞĚďǇWŚĂƐĞ//
ĞĂƐĞƐƚŚĞƉŽƚĞŶƚŝĂůĨŽƌWŚĂƐĞ/ŽǆŝĚĂƚŝǀĞKͲ
ƵƌŽŶŝĚĂƚŝŽŶ͕ĂŶĚŵĞƚŚǇůĂƚŝŽŶǀŝĂ +& 1 &+ &+
ŽŶ;ƉŽƚĞŶƚŝĂůůǇĨŽůůŽǁĞĚďǇWŚĂƐĞ//
+2
ŐůƵĐƵƌŽŶŝĚĂƚŝŽŶ͕ĂŶĚŵĞƚŚǇůĂƚŝŽŶǀŝĂ $QDORJ%
+2
$QDORJ%

Analog C: Insert fluoro substituent ortho to the methyl ether substituent.
This decreases the potential for Phase I aromatic hydroxylation (potentially
followed by Phase II sulfation, glucuronidation, and O-methylation catalyzed by
POMT).
ĨůƵŽƌŽƐƵďƐƚŝƚƵĞŶƚŽƌƚŚŽƚŽƚŚĞ +
+& 1
ďƐƚŝƚƵĞŶƚ͘
ŚĞƉŽƚĞŶƚŝĂůĨŽƌWŚĂƐĞ/ĂƌŽŵĂƚŝĐ
+& 1 2&+
ƉŽƚĞŶƚŝĂůůǇĨŽůůŽǁĞĚďǇWŚĂƐĞ//
)
ŽŶŝĚĂƚŝŽŶ͕ĂŶĚŵĞƚŚǇůĂƚŝŽŶǀŝĂ
+2
$QDORJ&


Fluorine
H-bond acceptor
Tolvaptan
There are a number of other functional groups that can undergo metabolic Demeclocyc
transformation (e.g., oxidative N-dealkylation of the secondary or tertiary amines;
benzylic oxidation of the carbon atoms attached to aromatic hydrocarbon);
however, isosteric modification is not available. In these cases, other strategies
can be employed (e.g., steric hindrance) to limit the potential for metabolic
transformation at these sites.
Page 82, Question 7: Replacement figure for tetrahydrocanibinol
7. Part A: Each of the structural requirements has been boxed and labeled.
B
4
3 A
Tetrahydrocannabinol
D: not a requirement; not present

E: not a requirement; not present

Part B: This analog meets nearly all of the structural requirements to have
cannabinoid activity. Unfortunately, it does not contain the benzopyran ring
system and, therefore, is devoid of cannabinoid activity. Based on what we
learned in Chapter 7, the benzopyran ring system likely provides much needed
Part B: Thisconformational
analog meets restriction
nearly all to
of allow for the correct
the structural spatial orientation
requirements to have of the rest of activity.
cannabinoid
the functional groups. This conformational restriction permits the functional groups
to optimally interact with the cannabinoid receptor.
C
F
D
Tetrahydrocannabinol analog
A: Required; not present

E: Not required; not present

CHAPTER 10
Aliskiren
1. Functional group names and other information provided below.
Function
Character Amino Acids That

Function Can Interact with
Acidic, Function the Functional
Contribute
Basic, or to Aqueous Interaction(s) Group via Ion–
Character Neutral Dipole Interactions
Solubility Possible with
Name of Hydrophilic Provide and/or Biological Target at pH=7.4.
Functional and/or pKa When Contribute to at Physiological None Is
Group Hydrophobic Relevant Absorption. pH=7.4 Acceptable.
A Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A) Lys, Arg
Hydrophobic (R) Absorption (R) Dipole–dipole
Ion–dipole (as the
dipole)
B Aromatic Hydrophobic Neutral Absorption Hydrophobic None
hydrocarbon van der Waals
π-π stacking
Cation-π
C Aliphatic Hydrophobic Neutral Absorption Hydrophobic None
alkane van der Waals
D Primary Hydrophilic Basic Solubility (NH2) Ion–dipole (as the Ser, Thr, Cys, Tyr,
amine (NH2) pKa ~9–11 Absorption (R) ion) Asn, Gln, His, Trp
Hydrophobic (R) Ionic
E Secondary Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A + D) Asp, Glu, Lys, Arg
alcohol Hydrophobic (R) Absorption (R) Dipole–dipole
Ion–dipole (as the
dipole)
CHAPTER
F
10
Amide Hydrophilic
(CONH2)
Neutral Solubility
(CONH2)
H-bonding (A) Asp, Glu, Lys, Arg
Dipole–dipole
Aliskiren Ion–dipole (as the
dipole)
2 Chiral carbon
R = carbon atoms have been circled.
scaffolding.
2. Chiral carbon atoms have been circled.
Aliskiren

If there are two or more chiral carbon atoms, then is possible for the drug to have
If there are two or more chiral carbon atoms, then it is possible for the drug to
have diastereomeric forms. In the case of aliskiren, there are four chiral carbon
Aliskiren
atoms; therefore, there are a lot of potential diastereomeric forms. A quick
reminder on how to determine if a pair of isomers is diastereomeric—if one
chiral carbon is held constant (e.g., R-isomer) and you vary at least one additional
If there are twocarbon,
chiral or more chiral
then the carbon atoms,will
pair of isomers then
beisdiastereomeric
possible for the drug
to one to have
another. In the
example below, the chiral center that is circled is held constant and the (*) chiral
center is varied. The pair of isomers drawn are diastereomers.
For geometric isomers to be possible there must be restricted rotation around a

carbon–carbon bond (e.g., presence of a double bond or alicyclic ring). Evaluation
of aliskiren reveals the absence of double bonds and alicyclic rings; therefore,
geometric isomers cannot exist.
3. Oral bioavailability is dependent on the drug’s ability to dissolve in the aqueous

contents of the gastrointestinal (GI) tract and its ability to cross the lipid bilayer
membrane. The hydrophilic character of the drug promotes aqueous solubility.
Evaluation of the entire molecule (not just the boxed functional groups) for
hydrophilic character reveals two ethers, two amides, a primary amine (in its
ionized form), and a secondary alcohol that will contribute meaningfully to the
hydrophilic character of the drug. (NOTE: the drug is sold as a hemifumarate salt
that further increases the overall water solubility of the drug). The hydrophobic
character of the drug promotes absorption across the lipid bilayer. Evaluation
of the entire molecule (not just the boxed functional groups) for hydrophobic
character reveals an aromatic hydrocarbon, a lipophilic ether, and several aliphatic
alkanes. The drug is formulated as a water-soluble salt and has ample hydrophilic
character. Unfortunately, it does not have sufficient hydrophobic character to allow
for meaningful absorption.

4. Metabolic transformations and identification of oxidative or non-oxidative

provided below.
Name of Metabolic Transformation Oxidative or Non-oxidative

A Oxidative O-dealkylation Oxidative
B Alcohol oxidation Oxidative
C Oxidative deamination Oxidative
D Oxidative O-dealkylation *
Oxidative
E Amide hydrolysis* Non-oxidative
1. Functional groups mimicking Leu and Val are circled. The non-hydrolyzable
*
This metabolite has been identified as one of the two primary metabolites produced.
hydroxyethylene group is boxed.
5. Functional groups mimicking Leu and Val are circled. The non-hydrolyzable
hydroxyethylene group is boxed.
6. It is important to first determine whether these drugs are basic, acidic, or

Aripiprazole amphoteric in nature. Based on a structural evaluation of the entire aliskiren
molecule (not just the boxed functional groups), there is one basic functional
1. Acidic and basic(primary
group function groups
amine) andare
noidentified along with
acidic functional ranges
groups and The
present. ionization
same state at pH =
evaluation for amlodipine yields identification of two basic functional groups
(primary amine and dihydropyridine ring) and no acidic functional groups. Based
Tertiary amine
on this evaluation, (Basic
both drugs arefunctional both would be bound to α1-acid
basic, andgroup)
Normal
glycoprotein pKa range
(plasma = It
protein). 9 is
toimportant
11 to remember that plasma protein
binding interactions are likely to happen when
Would be primarily ionized at a pH of a drug
5.6 is >90% plasma protein
bound. Given the extent to which amlodipine is plasma protein bound, it is highly
likely that a plasma protein binding interaction will occur when aliskiren displaces
amlodipine from the glycoprotein binding site. When this type of interaction
occurs, there will be a greater fraction of amlodipine present in its unbound form.
This leads to an increase in pharmacological activity resulting in hypotension
(excessively low blood pressure).
Aripiprazole
Aromatic amine (Aniline, Basic functional group)

Normal pKa range = 2 to 5
Would be primarily unionized at a pH of 5.6

Aripiprazole
Aripiprazole
1. Acidic
1. and basic
Acidic andfunction groupsgroups
basic function are identified alongalong
are identified withwith
ranges and and
ranges ionization state at pH =
ionization
state at pH = 5.6.
Tertiary amine (Basic functional group)

Would be primarily ionized at a pH of 5.6
Aripiprazole
Aromatic amine (Aniline, Basic functional group)

Would be primarily unionized at a pH of 5.6
2. All other functional groups are identified along with their water or lipid nature.
2. All other functional groups are identified along with their water or lipid nature.
Alkyl (aliphatic) chain

(Lipid soluble)
Ether oxygen
Halogens (Water soluble) Amide
(Lipid soluble) (Water soluble)
Hydrocarbon portion
of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring
(Lipid soluble)
Aripiprazole

(Lipid soluble)
3. 3.
Shown below
The are two
tertiary examples
amine, of water-soluble
aromatic organic and
amine, amide, salts ether
using lactic
oxygenacid atom
and citric
provide
adequate water solubility that allows aripiprazole to dissolve in the aqueous
contents of the gastrointestinal (GI) tract. Once dissolved, aripiprazole must
pass through the GI mucosal membrane to enter the blood stream. The dichloro
phenyl ring, the alkyl chain, and the hydrocarbon portion of the bicyclic ring will
provide adequate lipid solubility to allow for absorption. The tertiary amine will be
primarily ionized within the GI tract, whereas the aromatic amine will be primarily
unionized once it leaves the stomach. Remember that ionization is an equilibrium
process with some fraction of unionized molecules present at all times. According
to Le Chatelier’s principle, as soon as one unionized molecule passes through the
Aripiprazole lactate Aripiprazole citrate

GI membrane, the equilibrium will reset to provide additional unionized molecules.

This same principle also allows ionizable functional groups to penetrate the blood
brain barrier and enter the central nervous system (CNS). The same functional
groups that allowed aripiprazole to pass through the GI mucosal membrane will
also provide sufficient lipid solubility to allow it to cross the blood brain barrier and
reach its target receptors within the CNS.
4. Aromatic amines are much less basic than primary, secondary, and tertiary aliphatic
or alicyclic amines. The reason for this decreased basicity lies in the fact that an
aromatic amine can donate its lone pair of electrons, through resonance, into the
aromatic ring, thus making these electrons less available to bind with a proton.
Within the structure of aripiprazole, the nitrogen atom of the aromatic amine
is directly adjacent to ortho and meta chlorine atoms. Chlorine has a higher
electronegativity than nitrogen and, through induction, each acts as an electron
withdrawing group. This further decreases the availability of the lone pair of
electrons on the nitrogen, resulting in a decrease in basicity. Thus, the pKa for this
particular
2. All other aromatic
functional amine
groups are would
identified be with
along expected to be
their water at the
or lipid lower end of this range
nature.
(i.e., closer to 2).

(Lipid soluble)
5. The answer here is No. Tolbutamide and losartan
Ether oxygenare acidic drug molecules, due
to the presence of an acidic sulfonylurea
Halogens andsoluble)
(Water an ionizable tetrazole functional
Amide
group, respectively.(Lipid soluble)
Aripiprazole is a basic drug molecule due to the(Water soluble)
presence
of a tertiary amine and an aromatic amine. Acidic drug molecules primarily bind
to albumin, whereas basic drug molecules primarily bind to a1-glycoprotein. Hydrocarbon portion
Plasma protein binding interactions (also known as plasma protein displacement of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring
interactions) occur due to the nonspecific nature of the plasma proteins that bind
(Lipid soluble)
and transport drug molecules. These types of interactions are only therapeutically
important when the drug molecules are highly plasma protein bound (i.e., over
Aripiprazole
90%). Although this is true of all three drugs, the difference in their acid/base
nature significantly decreases the probability of a drug interaction due to plasma
protein displacement. (Lipid soluble)
6. Shown below are two examples of water-soluble organic salts using lactic acid and
3. Shown below
citric are two
acid. examples
There of water-soluble
are a number organic
of other salts using lactic
water-soluble acid acids
organic and citric
that could be
used (e.g., fumaric acid, malic acid, maleic acid, tartaric acid).
Aripiprazole lactate Aripiprazole citrate

7. There are only two methylene groups that would be expected to generate a chiral
center via metabolism: the benzylic carbon atom and the carbon atom adjacent
to the sp2 carbonyl. Oxidation at either of these two positions will add a hydroxyl
group and generate a chiral center. Oxidation of carbon atoms 1–5 will lead
to oxidative N-dealkylation and the initial formation of an aldehyde. Similarly,
4. There are only two
oxidation methylene
of carbon groups
atom that would
8 will lead be expected
to oxidative to generate
O-dealkylation a chiral
and the initialcenter
formation of an aldehyde. Oxidation of methylene groups in the middle of an alkyl
chain and adjacent to an sp2 hybridized center generally does not occur.
10
Adjacent to
8 sp2 carbon atom
9
1 2 6
7
5 Benzylic
3 4
Aripiprazole
4. There are only two methylene groups that would be expected to generate a chiral center
5. One example is shown below. Other binding interactions are possible among these four
8. One example is shown below. Other binding interactions are possible among
these four functional groups and four amino acids.10Isoleucine could form van der
Adjacent to
Waals and hydrophobic interactions 8 with the halogenated 2 aromatic ring, whereas
sp carbon atom
9
tyrosine could form1 the2 same6 types of interactions with the alkyl chain. Aspartic
acid could form an ion-dipole interaction
7 (as the ion) with the amide, whereas
5
glutamine could form an ion-dipole Benzylic
interaction (as the dipole) with the ionizedGln
3 4
tertiary amine. Please note that it is possible for tyrosine to form hydrogen bonds
Aripiprazole
with the amide and an ion-dipole interaction (as the dipole) with the ionized
tertiary amine. However, in the scenario given in this question, if tyrosine was used
to example
5. One form anisinteraction with
shown below. either
Other the interactions
binding amide or the Asp
are ionized among
possible tertiary amine,
these four neither
aspartic acid or glutamine could be used to form van der Waals and hydrophobic Hydrogen Bond
interactions with the halogenated aromatic ring.
Ionic Bond
Gln
van der Waals

Hydrophobic Interaction Asp
SS Stacking van der Waals
Hydrogen Bond
Charge Transfer Interaction Hydrophobic Interaction
Ionic Bond
Ile
van der Waals

Tyr
Hydrophobic Interaction
SS Stacking van der Waals
Charge Transfer Interaction Hydrophobic Interaction
Ile
Tyr

9. Metabolite A: Aromatic hydroxylation, Phase I
Note: This is somewhat of an unexpected metabolite because the presence of

halogen substituents on the aromatic ring generally deactivates these rings from
oxidation. The difference in this particular drug molecule is the presence of an
adjacent aromatic amine. This aromatic amine can donate electrons into the ring
via resonance and either override or neutralize the electronic effects of the chloro
groups, thus allowing for aromatic hydroxylation.
Metabolite A: Aromatic oxidation, Phase I
Metabolite B: Benzylic oxidation, Phase I
Metabolite B: Benzylic oxidation, Phase I
Note: Due to the ability to form a conjugated system, this secondary hydroxyl
group readily undergoes dehydration to form the following metabolite.
Dehydration allows
conjugation between
the amide and the
aromatic ring.
Metabolite C: Oxidative N-dealkylation followed by oxidation of the resulting

aldehyde to a carboxylic acid by aldehyde dehydrogenase, Phase I
onorgestrel
art B: In levonorgestrel there are several places where the trans designation is relevant. Each
Levonorgestrel
e following shows a unique trans relationship within levonorgestrel.
1. Answers provided below.
Function
Character Contribute to Aqueous Solubility or
Name of Functional Group Hydrophobic, Hydrophilic, or Both Absorption
A Ketone Hydrophobic (R) Absorption (R)
Hydrophilic (C=O) Solubility (C=O)
B Alkene Hydrophobic Absorption
C Cycloalkane Hydrophobic Absorption
D Alkyne Hydrophobic Absorption
E Tertiary alcohol Hydrophobic (R) Absorption (R)
Hydrophilic (OH) Solubility (OH)
Levonorgestrel
R = carbon scaffolding. Levonorgestrel Levonorgestrel
2. Both the ketone and tertiary alcohol contain electronegative oxygen atoms, which
inductively attract/withdraw electron density from the carbon atoms attached
to them. This means that both the tertiary alcohol and ketone are electron
withdrawing groups based on an inductive effect.

The tertiary alcohol is attached to aliphatic carbons and therefore cannot

participate in any resonance effects. The ketone is part of an α, β unsaturated
ketone and there is a limited amount of resonance contribution as an electron
withdrawing group.
3. Levonorgestrel has several functional groups that are exclusively hydrophobic in

character. This should promote absorption (lipid solubility) across the skin if the
drug is formulated as a patch. Distribution into the plasma is facilitated by both
the ketone and tertiary alcohol which are both hydrophilic in character and able
to participate in H-bonding with water due to the electronegativity differences
between the C and O atoms or O and H atoms (respectively). This hydrophilic
character will contribute to aqueous solubility in the blood.
Because levonorgestrel has functional groups that contribute to both the

hydrophobic and hydrophilic character (as just described) of the drug, it is
possible for it to be administered orally. Dissolution and solubility in the aqueous
contents of the stomach, as well as distribution into the plasma are facilitated
by those functional groups that contribute to the hydrophilic character of the
drug. Absorption across the lipophilic GI membranes and then across target
cell membranes is facilitated by those functional groups that contribute to the
hydrophobic character of the drug.
4. In Chapter 3 we described a nonelectrolyte as a drug that does not dissociate into

ions in solution (contains only neutral functional groups) and an electrolyte as a
drug that does dissociate into ions in solution (contains one or more acidic or basic
functional groups and/or a quaternary amine). Levonorgestrel is a nonelectrolyte. It
does not contain any ionizable (acidic or basic) functional groups and is comprised
only of neutral functional groups.
5. In Chapter 3 we discovered that human serum albumin (albumin) binds to a

variety of endogenous substances and drugs. It is fairly nonspecific in its binding
requirements, although prefers to interact with acidic molecules more so than
basic molecules and prefers to interact with drugs that are hydrophobic in
character more so than those that are hydrophilic in character. Levonorgestrel
has no acidic or basic functional groups, but is comprised of functional groups
that contribute a significant amount of hydrophobic character. Because of this
hydrophobic character, levonorgestrel is suitable for binding to albumin.
6. In Chapter 5 we learned that log P represents a ratio of the solubility of the

unionized drug in an organic solvent to the solubility of the same unionized drug
in an aqueous environment. The structural evaluation of levonorgestrel reveals
that this drug is unable to be ionized, so we are really looking at the ratio of the
solubility of the drug in an organic solvent to the solubility of the same drug in an
aqueous environment.

Part A:
If we want the log P value to decrease, we would need to increase the amount of
drug that is soluble in an aqueous environment (larger denominator in the ratio).
This means that our structural modification should add hydrophilic character to
the drug molecule. In Chapter 5 we learned that a water-soluble prodrug could
be created (e.g., create a sodium phosphate salt or a sodium succinate salt). The
prodrug will be metabolically cleaved to reveal the parent drug. Another solution
is to modify the drug structure by adding one or more hydrophilic functional
groups (e.g., alcohol, amine). A word of caution with this last recommendation—
functional group addition must not interfere with the critical binding interactions
between a drug and its biological target.
Part B:
If we modify the molecule to increase the hydrophilic character of the molecule,
then we will have also increased the water solubility of the molecule.
Part C:
Norgestimate has a log P = 4.11, which is larger than levonorgestrel. The
numerator represents the solubility of the drug in an organic solvent. So, from
a structural evaluation perspective, why is norgestimate more lipid soluble than
levonorgestrel? As you can see, the tertiary alcohol has been converted into a
lipid-soluble ester prodrug. This modification enhances the lipid solubility of the
drug and contributes to the increase in log P value. In addition, the ketone has
been converted into an oxime, which can be metabolically converted into the
parent ketone. The oxime is actually more water soluble than the parent ketone,
so this modification is not what is enhancing the lipid solubility and causing an
increase in the log P value.
7. Both ethinyl estradiol and levonorgestrel contain a hydrophobic steroid scaffold

(infrastructure) on which several substituents are positioned. The hydrophobic
steroid skeleton resides in the hydrophobic cavity found as part of both the
estrogen and progesterone receptors. Additional structural evaluation reveals that
levonorgestrel contains a ketone (H-bond acceptor) and a tertiary alcohol (H-bond
acceptor and donor) on opposite ends of the steroid skeleton. Ethinyl estradiol has
a phenol (H-bond acceptor and donor) and a tertiary alcohol (H-bond acceptor and
donor) on opposite ends of that steroid skeleton. Given that the estrogen receptor
requires that receptor agonists interact with both the hydrophobic cavity, as well as
via two critical H-bonding interactions, it is no surprise that levonorgestrel will have
some agonist activity at the estrogen receptor.
8. Part A: As you learned in Chapter 7, the trans designation refers to substituents

being located on opposite sides of a double bond or ring system in geometric
isomers.
Part B: In levonorgestrel there are several places where the trans designation
is relevant. Each of the following shows a unique trans relationship within
levonorgestrel.

8. Part B: In levonorgestrel there are several places where the trans designation is relevant. Each
of the following
568 shows
BASIC CONCEPTS IN trans
a unique relationship
MEDICINAL within levonorgestrel.
CHEMISTRY
Levonorgestrel Levonorgestrel Levonorgestrel
Levonorgestrel
Levonorgestrel (trans: ethyl and ethynyl groups)
Parts C and D: When functional groups are cis to one another, they are found on the
same side of a double bond or ring system. In the case of the levonorgestrel analog
that has a mixture of cis/trans relationships, there are several cis relationships, two of
which are boxed. Only one of these, box #1, has an effect on the overall shape of the
steroid skeleton. As you can see from the picture below, the steroid is no longer flat
as a result of the cis ring junction found in box #1. This would make interaction with
the progesterone receptor’s hydrophobic cavity less than optimal. Not only is the
steroid skeleton a different shape, but the ketone is now located in a different place
in space and is unlikely able to interact via H-bonding with the estrogen receptor. For
both types of receptors, this cis configuration places a hydrophilic functional group
(ketone) in the space that should be occupied only with hydrophobic functional
Parts Cgroups.
and D:(Note:
WhenThe structure
functional activity
groups arerelationships (SARs) they
cis to one another, for the
areprogesterone
found on the same side
receptor require the presence of the double bond in the A ring, so this analog does
not bind to and activate the progesterone receptor.)
2
1 H3C
H OH
H
C CH
H
H
H
O
cis/trans Mixture

9. Part A:
As we learned in Chapter 8, a drug that is subject to first-pass metabolism is
metabolized by the liver prior to reaching systemic circulation. This decreases
the amount of drug that is bioavailable. Drugs that are lipid soluble are typically
subject to first-pass metabolism.
Part B:
As we identified earlier in this evaluation, levonorgestrel contains a significant
amount of hydrophobic character. You might have expected that it was sufficiently
hydrophobic to undergo first-pass metabolism.
Part C:
Possible Phase I transformations: allylic oxidation; epoxidation/peroxidation;
reduction
Possible Phase II transformations: glucuronidation; sulfation (minor)
Nadolol and Other β-Adrenergic Antagonists

1. Functional group names and hydrophilic or hydrophobic character provided below.
Functional Group Name Hydrophilic or Hydrophobic

A Secondary hydroxyl Hydrophilic due to its ability to form hydrogen bonds with water as either a
(secondary alcohol) donor or an acceptor.
B Ether oxygen Hydrophilic due to its ability to form hydrogen bonds with water as an
acceptor.
C Alkyl group; alkyl chain; Hydrophobic due to its inability to ionize or form hydrogen bonds with
aliphatic chain water; hydrocarbon functional groups enhance lipid solubility.
D Secondary amine Hydrophilic due to its ability to ionize and form ion dipole-interactions with
water and to participate in hydrogen bonds with water as either a donor or
an acceptor in its unionized form.
E Alkyl group; t-butyl group Hydrophobic due to its inability to ionize or form hydrogen bonds with
water; hydrocarbon functional groups enhance lipid solubility.
F Aromatic ring; phenyl ring Hydrophobic due to its inability to ionize or form hydrogen bonds with
water; hydrocarbon functional groups enhance lipid solubility.
2. Epinephrine is a naturally occurring hormone that acts as an agonist on both α

and β adrenergic receptors. The secondary amine, the secondary hydroxyl group,
and the phenolic hydroxyl groups present within the structure of epinephrine
provide key binding interactions with both the α and β adrenergic receptors. As
discussed in Chapter 9, replacement of the N-methyl group of epinephrine with
a larger alkyl group, such as the t-butyl group on nadolol provides selectivity for
β adrenergic receptors due to a steric effect. The secondary amine, methylene,
and secondary hydroxyl group of nadolol provides an atom-for-atom mimic of
epinephrine. The major difference in these two structures lies in the spacing
between the basic nitrogen atom and the aromatic ring systems, as well as the
positioning/orientation of the phenolic or alicyclic hydroxyl groups. The orientation
seen in epinephrine produces an agonist effect when it binds to the β adrenergic
receptor, while the larger bicyclic ring system produces an antagonist effect.

2
570
Epinephrine is a naturally occurring hormone that acts as an agonist on both D and
BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Atom for atom

match Atom for atom
match
Smaller Larger
Nonspecific Specific for E receptors
Optimal binding Altered binding and spacing

for agonist effect provides antagonist effect
3. Epinephrine is a naturally occurring endogenous agonist at the β adrenergic

receptors. The structure of epinephrine contains one chiral center with an R
configuration that maximizes the binding interactions of the secondary hydroxyl
group with the adrenergic receptors. In examining the four stereoisomers, the
secondary hydroxyl groups in isomers A-2 and B-1 have the same stereochemistry
as that seen in epinephrine and would be expected to exhibit better binding and
1. Epinephrine is a naturally
pharmacological occurring
activity than endogenous agonist
those that had at the E adrenergic
the opposite receptors.
stereochemistry. This The
is
illustrated below.
Isomer A-2
Need to mimic this portion of
norepinephrine, including stereochemistry
180 degree rotation

at the indicated bond
The stereochemistry of isomer A-2 (and B-1)

at the secondary hydroxyl group mimics
the stereochemistry of epinephrine
The use of salts and esters are two common chemical strategies used to enhance the oral

O
4. The use of salts and esters are two common chemical strategies used to enhance
the oral absorption of a drug. Inorganic salts and water-soluble organic salts are
commonly used to enhance the dissolution of a drug, while lipid-soluble esters
are commonly used as prodrugs to enhance the
The stereochemistry lipid solubility
of isomer A-2 (and of drugs. Based on
B-1)
its low log P value, it appears at the
thatsecondary hydroxyl
nadolol has group water
sufficient mimics solubility, but lacks
the stereochemistry
sufficient lipid solubility to traverse of epinephrine
the GI membranes. Thus, the use of lipid-
soluble esters could be used to obtain a better water/lipid solubility balance. The
alicyclic
The use of saltshydroxyl
and estersgroups
are twoare a littlechemical
common less sterically
strategieshindered than thethe
used to enhance secondary
oral
hydroxyl group in the alkyl chain and could be esterified. Two examples of lipid-
soluble esters of isomer B-1 are shown below.
O
O N O
H
H3C O OH O N
H
O OH
H3C O
HO
O
Diacetyl prodrug Phenylacetyl prodrug
of nadolol of nadolol
5. Both nadolol and atenolol share a key structural backbone that is found in all
β-blockers. This backbone has been boxed in the structures below. The two
structural differences are the N-alkyl groups and the substitutions on the respective
aromatic rings. It can thus be concluded that one or both of these differences is
responsible for the β1 adrenergic receptor selectivity. Although this question assumes
no prior knowledge of β-blocker SAR, you should be able to postulate potential
binding differences. The isopropyl group of atenolol may optimize interactions
with the β1 receptor, while the larger and slightly more bulky t-butyl found within
the structure of nadolol does not. Similarly, the location and availability of functional
groups capable of hydrogen bonding interactions may optimize binding interactions
with the β1 receptor. Both nadolol and atenolol have functional groups capable of
acting as both hydrogen bond donors and/or acceptors; however, the amide present
within the structure of atenolol is para to the ether oxygen atom, while the alicyclic
hydroxyl groups within the structure of nadolol are oriented in a different direction.
Additionally, the amide functional group is located on a flexible alkyl chain, while
the alicyclic hydroxyl groups have a more ridged conformation. The combination
of Page
these95, bottom schematic: The words were cut-off
structural differences and binding interactions may contribute to atenolol’s
selectively in blocking the β1 adrenergic receptor.
Common structural feature
for all E-blockers
Difference 1
Smaller N-group
Nadolol Atenolol
Difference 2
Position and flexibility of
hydrogen bonding functional groups

6. Binding interactions and corresponding amino acids provided below.
Functional Amino Acids Capable of Forming Specific

Group Types of Binding Interactions Binding Interactions*
A Amide Ion-Dipole (as the Dipole) Asp, Glu (with carbon atom or hydrogen
atoms); Arg, Lys, His** (with oxygen or
nitrogen atoms) of the amide
Dipole-Dipole Ser, Thr, Tyr, Cys, Asn, Gln, His**
Hydrogen Bond (Donor and/or Acceptor) Ser, Thr, Tyr, Cys, Met, Asn, Gln, Trp, His**
B Phenyl ring; van der Waals; Hydrophobic Tyr, Phe, Trp (better interaction***); Val, Leu,
aromatic ring; Ile, Met, Ala
aromatic
π-π Stacking Tyr, Phe, Trp, His
hydrocarbon
Cation-π Interaction Arg, Lys, His (less likely*)
C Secondary Ion-Dipole (as the Dipole) Asp, Glu (with hydrogen of hydroxyl); Arg,
hydroxyl Lys, His** (with oxygen of hydroxyl)
Dipole-Dipole Ser, Thr, Tyr, Cys, Asn, Gln, His**
Hydrogen Bond (Donor and/or Acceptor) Ser, Thr, Tyr, Cys, Met, Asn, Gln, Trp, His*
D Secondary Ionic Asp, Glu
amine
Ion-Dipole (as the Ion) Ser, Thr, Tyr, Cys, Asn, Gln
E Alkyl group; van der Waals; Hydrophobic Val, Leu, Ile, Ala (better interaction***); Tyr,
aliphatic Phe, Trp
hydrocarbon
*
At a pH of 7.4, the side chains of Glu, Asp, Lys, and Arg will be primarily ionized; therefore, they can only participate
in ionic bonds and ion-dipole interactions (as the ion).
**
The side chain of histidine is primarily unionized at a pH = 7.4. The small fraction that is ionized could form an ion-
dipole interaction with a partially negatively charged atom, while the unionized fraction can serve as a hydrogen bond
donor or acceptor. Additionally, in its unionized form it can serve as the dipole in an ion-dipole interaction.
Stronger van der Waals interactions occur when alkyl chains interact with alkyl chains; however, all of the listed amino
***
acids could possibly interact with the indicated functional group.
7. In comparing the structures of propranolol and nadolol, there are two sites of
structural variation. The t-butyl group within the structure of nadolol is slightly
larger and more lipid soluble than the isopropyl group within the structure of
propranolol; however, the major difference lies in the ring systems. The structure of
propranolol contains a lipid-soluble, bicyclic naphthalene ring, while the structure
of nadolol contains a more water-soluble bicyclic ring. The two alicyclic hydroxyl
groups within the structure of nadolol can form hydrogen bonds with water, an
interaction not possible with propranolol. Thus, propranolol is expected to be
more lipid soluble than nadolol. A comparison of their respective log P values
verifies this expectation. The log P value for nadolol is 1.3 (given in Question 4),
and the log P value for propranolol is 3.1. Since lipid-soluble drugs are more likely
to undergo extensive first-pass metabolism than water-soluble analogs, it can be
concluded that propranolol is extensively metabolized while nadolol is excreted
unchanged. Additionally, because propranolol is more lipid soluble than nadolol,
it can better penetrate the blood brain barrier and provide beneficial effects in the
treatment of migraine headaches and anxiety.

3. In comparing the structures of propranolol and nadolol,
APPENDIX: thereTO
ANSWERS areCHAPTER
two sitesQUESTIONS
of structural 573
Isopropyl t-Butyl
Naphthalene
Propranolol Nadolol
Tetrahydronaphthalene-2,3-diol
4. Part A: Hydrolysis of the amide followed by acetylation of the resulting aromatic amine.
8. Part A: Hydrolysis of the amide followed by acetylation of the resulting aromatic
Part B: amine.
4. Part A: Hydrolysis
Part B: of the amide followed by acetylation of the resulting aromatic amine.
Part B: Pathway A: Oxidative deamination is a Phase I transformation. YES. Although
H for secondary amines, oxidative
direct oxidative deamination is possible
N-dealkylation to a primary amine normally occurs prior to oxidative deamination.
O O O H 2N
H
OH
O O O H 2N
OH
HN
O
HN
O
Pathway B: Reduction: Phase I, YES

Pathway C: Benzylic oxidation is a Phase I transformation. NO, it is not possible

for acebutolol because the only benzylic carbon atom is a ketone and lacks a
Pathway D: Oxidative
hydrogen O-dealkylation is a Phase I transformation. YES, it is possible;
atom.
Pathway D: Oxidative O-dealkylation is a Phase I transformation. YES, it is possible;

Pathway
D: Oxidative
Pathway O-dealkylation
D: Oxidative is a Phase
O-dealkylation I transformation.
is a Phase YES,YES,
I transformation. it is possible;
it is
possible; however, due to the location of the ether oxygen atom, it is sterically
hindered and the probability of this metabolic transformation is low.
Pathway E: Sulfate conjugation: Phase II, YES.
5. In comparing the structures of esmolol, acebutolol, and atenolol, it is found that the structure
9. In comparing the structures of esmolol, acebutolol, and atenolol, it is found that
the structure of esmolol contains an ester functional group, while the structures of
acebutolol and atenolol contain amide functional groups. Esterase enzymes are
readily available within the human body and can quickly hydrolyze ester functional
groups. The hydrolysis of esmolol is shown below. The metabolite is inactive due
5. In comparing
to thethe
factstructures of esmolol,
that its binding acebutolol,
interactions and
with the β1 atenolol, it is found
receptor have that the structure
been significantly
altered. An ionized carboxylic acid is unable
Hydrolysis to form the same binding interactions
with the β1 receptor as the original ester and is thus inactive.
Esmolol
Hydrolysis
Ofloxacin
5. Part A: Ofloxacin can be formulated as both a hydrochloride and as a sodium salt. Both types
of inorganic salts willEsmolol
enhance the water solubility of the drug.
Ofloxacin
-
5. Part A: Ofloxacin can be formulated as both a hydrochloride and as a sodium salt. Both types
Ofloxacin
Contributes to Aqueous Solubility

Name of Functional Group Hydrophobic and/or Hydrophilic and/or Absorption
A Tertiary amine + aniline/ Hydrophobic (R) Absorption (R)
aromatic amine Hydrophilic (both N atoms) Solubility (both N atoms)
(piperazine)
B Halogen Hydrophobic (R) Absorption (R)
Hydrophilic (F) Solubility (F)
C Aniline Hydrophobic (R) Absorption (R)
Hydrophilic (N) Solubility (N)
D Ketone Hydrophobic (R) Absorption (R)
Hydrophilic (C=O) Solubility (C=O)
E Carboxylic acid Hydrophobic (R) Absorption (R)
Hydrophilic (COOH) Solubility (COOH)
F Alkene Hydrophobic (R) Absorption (R)
G Ether Hydrophobic (R) Absorption (R)
Hydrophilic (O) Solubility (O)
2. Part A: halogen; ether (inductive); ketone; carboxylic acid

Part B: ketone (carbon atom)
Part C: piperazine (tertiary amine + aniline/aromatic amine)
Part D: ether (resonance), aniline (resonance)
Name of Functional Group Acidic, Basic, or Neutral pKa Value/Range

A Piperazine Basic pKa 9–11 (methylated N atom)
pKa 2–5 (aniline/aromatic amine)
B Halogen Neutral
C Aniline Basic pKa 2–5
D Ketone Neutral
E Carboxylic acid Acidic pKa 2.5–5
F Alkene Neutral
G Ether Neutral
Because ofloxaxin contains at least one acidic and one basic functional group, it is
considered amphoteric.

Pathway
4. Functional group E: Sulfate
ionization conjugation:
at different Phase II,
pH environments YES. below.
shown
pH = 2 pH = 7.4 pH = 5 pH = 8.5
Name of Functional Group (stomach) (plasma) (urine) (large intestine)
Piperazine (CH3) Ionized Ionized Ionized Ionized
Piperazine* Ionized Unionized 50%/50% Unionized
(Aniline/aromatic amine)
Aniline Ionized Unionized 50%/50% Unionized
Carboxylic acid Unionized Ionized 50%/50% Ionized
*Note: Only one of the two nitrogen atoms in this piperazine ring will be ionized at a time. The more basic nitrogen
atom, and the one that is more likely to be ionized, is the nitrogen atom with a methyl substituent.
Part A:
There are four possible atoms/functional groups that can be ionized in any
given pH environment. In the urine (pH = 5), all four functional groups are either
5. In comparing the structures of esmolol, acebutolol, and atenolol, it is found
primarily ionized or are at least 50% ionized. This confers considerable hydrophilic
character to the molecule [that already has a number of functional groups that are
hydrophilic in character (halogen, ketone, ether) but are not ionizable], making
it remarkably water soluble. As a result, elimination via the kidneys is expected,
without the need for any Phase I or Phase II metabolism.
Part B:
Conducting a similar qualitative evaluation at pH = 6.5, we find that two of the
Hydrolysis
four atoms/functional groups will be predominantly ionized at pH = 6.5. This will
confer considerable water solubility to a molecule that already has a number of
functional groups that are hydrophilic in character (halogen, ketone, ether) but are
not ionizable. The considerable hydrophilic character makes the molecule suitable
for delivery as an aqueous solution.
Piperazine (CH3) Primarily Esmolol ionized
Piperazine (aniline/aromatic amine) Primarily unionized
Aniline Primarily unionized
Ofloxacin
Carboxylic acid Primarily ionized
5. Part A: Ofloxacin can be formulated as both a hydrochloride and as a sodium
of inorganic salts will enhance the water solubility of the drug.
5. Part A: Ofloxacin can be formulated as both a hydrochloride and as a sodium salt.
Both types of inorganic salts will enhance the water solubility of the drug.
Part B: Ofloxacin could be modified to form a lipid-soluble salt (e.g., benzathine

or stearate salts). It could also be modified to form a lipid-soluble ester prodrug.

6. Part A:
The top half of ofloxacin has a fluorine atom, a ketone, and a carboxylic acid. At
physiological pH these functional groups will participate in H-bonding interactions
(H-bond acceptor) via the fluorine and ketone functional groups and ion-dipole
interactions (as the ion) with the carboxylic acid functional group (in its ionized
form).
Part B:
The bottom half of ofloxacin includes a piperazine, an ether, an aniline and
some hydrocarbon scaffolding. At physiological pH these functional groups will
participate in H-bonding interactions (H-bond acceptor) via the ether group, ion-
dipole interactions (as the ion) via the piperazine group (in its ionized form), and
through hydrophobic interactions with the hydrocarbon scaffolding present.
Part C:
The fluoroquinolones self-associate into two pairs at the biological target. Each
pair of drugs are stacked together via π-π stacking interactions. One drug pair then
interacts with the other drug pair via the interactions mentioned in part B.
. Part A: Chiral center has been circled.
7. Part A: Chiral center has been circled.
Ofloxacin
Part B: Enantiomers are possible at the chiral center. Diastereomers are not
possible,
aquinavir and Other HIV as there is Inhibitors
Protease only one chiral carbon. Geometric isomers are not possible,
as there are no double bonds or ring junctions that can adopt an alternate
. The most basic functional group
conformation. has been identified
Conformational isomers arealong withprimarily
possible pKa range andpiperazine
via the other
ring, as it can adopt either a boat or chair conformation.
Part C: Given that the chiral center is located on the bottom side of the molecule, it
Most Basic
is likely that the interactions associated withFunctional Group
drug pair associations will be affected
Tertiary Amine
by a change in stereochemistry at this center. Interactions with the DNA target will
not be affected by a change in Normal pKa range: 9 at
the stereochemistry tothis
11 center. Drug-drug pairing
Would in
will also be unaffected by a change bethe
primarily ionized at this
stereochemistry a pH of 2.3
center.
8. Part A: Ofloxacin is highly hydrophilic in character and has several functional

groups that are predominantly ionized in every physiological compartment. As a
result, it is considered very water soluble. First-pass metabolism typically occurs on
molecules that are highly hydrophobic in character and, therefore, it is unlikely that
ofloxacin would undergo first-pass metabolism. Given that ofloxacin has 98% oral
bioavailability, this confirms that first-pass metabolism does not occur.

Only Other Ionizable Functional Group
7. Part A:578
Chiral
centerCONCEPTS
BASIC has beenIN
circled.
MEDICINAL CHEMISTRY
Part B:
Phase I transformations: oxidative N-dealkylation; N-oxidation; oxidative
O-dealkylation; aromatic hydroxylation (ortho and para)
Phase II transformations: glucuronidation; amino acid conjugation
Part C:
Because ofloxacin is primarily excreted unchanged via a renal route and a small
portion undergoes liver-based metabolic transformations, patients diagnosed with
moderate-to-severe kidney and/or liver disease should not be given ofloxacin.
Ofloxacin
SaquinavirSaquinavir
and Other HIVand Other
Protease HIV Protease
Inhibitors Inhibitors
1. The most basicmost
1. The functional
basicgroup has been
functional identified
group alongidentified
has been with pKa range
alongand other
with pKa
range and other information.
Most Basic Functional Group
Tertiary Amine
Normal pKa range: 9 to 11
Only Other Ionizable Functional Group

Heterocyclic Amine (Basic functional group)
Normal pKa range: 1 to 5
Primary form would depend on the specific pKa
since a pH of 2.3 lies in the middle of this range
2. Water-soluble organic salts enhance the solvation, dissolution, and water

solubility of drug molecules. Therapeutically, this can contribute to enhanced oral
absorption as well as the preparation of concentration intravenous, ophthalmic,
and otic solutions. Shown below is a succinate salt of saquinavir.

3 Water-soluble organic salts enhance the solvation, dissolution, and water solubility of
3 Water-soluble organic salts enhance the solvation, dissolution, and water solubility of
3. The ability of a drug molecule to be orally absorbed from the GI tract into the
systemic circulation requires a balance between water- and lipid-soluble functional
4 The ability of a drug molecule to be orally absorbed from the GI tract into the systemic
groups. The water-soluble functional groups allow the drug to dissolve in the GI
tract, and the lipid-soluble functional groups allow the drug to pass through the GI
membrane and enter the systemic circulation. The lipid-soluble functional groups
4 The ability of astructure
within the drug molecule to be orally
of saquinavir absorbed
have been boxedfrom thePlease
below. GI tract into
note the
that systemic
while
the nitrogenQuinoline ringquinoline ring can participate in hydrogen bonds, this
atom of the
aromatic ring system (as a whole) enhances lipid solubility.
Quinoline ring
4. Saquinavir is able to inhibit HIV protease by acting as a stable mimic of the

substrate of the above reaction. The structure of saquinavir is largely peptidic in
nature as shown below. It contains three amide (i.e., peptide) bonds and functional
groups that either match or mimic the side chains of amino acids normally
found in the substrates for HIV protease. The labile peptide bond between
the phenylalanine and the proline residues has been replaced with a stable
hydroxyethyl group. The tetrahedral carbon atom (indicated with the asterisk)
that is attached to the secondary hydroxyl group provides a stable mimic of the
peptide bond hydrolysis intermediate. Due to these structural characteristics,
saquinavir is considered to be a peptidomimetic and is able to bind to the active
site of HIV. Since the labile bond has been replaced with a stable mimic, HIV
protease is not able to cleave the bond and is thus inhibited by the binding of
saquinavir.

5 Saquinavir
580
is able to inhibit HIV protease by acting as a stable mimic of the substrate of
BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Analog of Phe
Mimics Phe or
aromatic amino acid
O H
H
N H * Mimics Pro
N N N
O N H 2 OH H
O
O N
H
Asn
5. As discussed in the previous question, saquinavir acts as a stable mimic of the

substrates for HIV protease. In order to serve as a stable mimic of a protein, the
6 Thestereochemistry
information provided in theacids
of the amino question provides
(or amino acid multiple cluesmatch
analogs) must to the that
correct
of answers.
the naturally occurring amino acids. Chiral centers 1, 2, and 4 match the normal
stereochemistry found in naturally occurring L-amino acids; therefore, changing
the stereochemistry of any of these chiral centers would likely result in a decreased
5 Saquinavir
ability istoable to inhibit HIV
effectively protease
mimic by acting
a protein as a stableThe
substrate. mimic of the substrate ofof chiral center
stereochemistry
N H
3 is also essential as it provides a stable 2mimic of peptide bond hydrolysis. Chiral
centers
O 5 and 6 are partOof the bicyclic
Analog ofring
Phethat mimics proline. This bicyclic ring is
O O
O larger than
Mimics Phe or and the cis orientation of the hydrogen atoms more
proline, than likely O O
aromatic amino acid S O
Ooptimizes
N the bindingN of this larger ring to a hydrophobic pocket in the enzyme
Hydrolysis S
H site. While the stereochemistry of chiral
binding H centers 5 and 6 Omay not N be as N
H
essential asOthose at chiral
O
H centers 1-4, the optimal binding of this bicyclic ring OH
N H * Mimics Pro
would–have O Pbeen O Ntested and established
N in
N the development of saquinavir.
H
O– O N H 2 OH
Amprenavir
O
O N
6. The information provided in the question
Fosamprenavir
provides
multiple clues to the correct
H
answers. Fosamprenavir isAsn the prodrug, and amprenavir is the active metabolite.
The only difference in these names is the “Fos” prefix. Examining the structure of
fosamprenavir reveals the presence of a phosphate functional group. It can thus be
concluded that the phosphate group of fosamprenavir is removed to produce the
6 active
The information provided in the
drug amprenavir. Thequestion provides
metabolic multiple clues tothat
transformation the correct
removes answers.
a phosphate
group is a hydrolysis reaction.
N H2
N H2
O O
O O O
O S O
Hydrolysis O S
O N N
H O N N
O H
OH
–
O P O
O– Amprenavir
Fosamprenavir

The phosphate functional group enhances the water solubility of amprenavir.

Increasing the water solubility of a drug enhances its solvation and dissolution.
Page 95,This is schematic:
bottom required The
for words
oral absorption
were cut-off as well as the preparation of concentrated
solutions. Given that fosamprenavir is administered orally, this prodrug is used to
enhance the water solubility of amprenavir and to provide a better water-/lipid-
solubility balance for oral
Common absorption.
structural feature
for all E-blockers
Difference 1
Smaller N-group
7. The first step in comparing the structural similarities of drug molecules is to ensure
that all overlapping (or similar) functional groups are properly aligned. Because we
have already examined the structure of saquinavir, we will use this as our prototype
and leave it unaltered. In order to align the functional groups of amprenavir with
those of saquinavir, all that needs to be done is to rotate about the sulfonamide
nitrogen atom. This reveals an atom-for-atom match for a large portion of the
Nadolol Atenolol
structures of saquinavir and amprenavir (indicated by the polygons in the structures
below). BothDifference
drugs have 2 a mimic of Phe, a tetrahedral carbon atom that mimics
the transition
Positionstate of HIV of
and flexibility protease, and a mimic of Pro. Additionally, the distance
hydrogencarbon
between bondingAfunctional groups ring of saquinavir and the central t-butyl carbon
in the bicyclic
B is exactly the same as that seen between carbon A of amprenavir’s isobutyl chain
and the center of its aromatic ring (B). This indicates that these two hydrophobic
functional groups are located in similar positions and can provide similar binding
interactions (i.e., van der Waals interactions) with hydrophobic binding pockets
present within the structure of HIV protease. As a final note here, amprenavir was
initially drawn in a manner in which all of the functional groups did not overlap
with those of saquinavir. This was done intentionally. Drug structures that you will
encounter may look or be drawn differently, depending on the source. A key skill
to master is the ability to look at drug structures, identify the similarities, and if
Page 105, Question 7 (text
necessary, overlapped
redraw structure) so that you can easily compare them.
the structures
Mimics Phe
Mimics Phe
Mimics Pro
O H
Mimics Pro
H A
N H * O
N N N A
O
H H *
O NH2 O H O N N
O O
OH S
O B O
N
H
Saquinavir Amprenavir B
* Mimics tetrahedral carbon
of the transition state NH 2


8. Metabolic Path A: N-Oxidation; this metabolic transformation is primarily

catalyzed by FMO enzymes; however, it can be catalyzed by CYP3A4.
Metabolic Path B: Hydrolysis; this metabolic transformation is catalyzed by

hydrolase enzymes, not CYP3A4 isozymes.
Metabolic Path C: Omega-1 oxidation (or oxidation of aliphatic carbon atoms);

this metabolic transformation could be catalyzed by the CYP3A4 isozyme.
Metabolic Path D: Oxidative N-dealkylation; this metabolic transformation could

be catalyzed by the CYP3A4 isozyme.
Page 106, question 9

9. There are two sites of metabolism. It does not matter which site is metabolized
first; however, in both cases, step 1 must occur prior to step 2.
Step 1: Aromatic hydroxylation, phase I

Step 2: Glucuronide conjugation, phase II
Darunavir
Step 1: Oxidative O-dealkylation, phase I

Step 2: Reduction of resulting aldehyde, phase I
Sorafenib
Character Function Function

Character Acidic, Basic, or Contributes to Interaction(s)
Name of Hydrophilic Neutral. Aqueous Solubility Possible with Biological
Functional and/or Provide pKa If and/or Target at Physiological
Group Hydrophobic Relevant. Absorption pH (7.4)
A Halogenated Hydrophobic Neutral Absorption Cl:
aromatic Dipole-dipole
hydrocarbon Ion-dipole (as the dipole)
Ar:
van der Waals
Hydrophobic
π-π Stacking
Cation-π interaction
Charge transfer interaction

B Halogenated Hydrophilic (F) Neutral Solubility H-bonding (A)

aliphatic alkane Dipole–dipole
Ion–dipole (as the dipole)
C Urea Hydrophilic Neutral Solubility H-bonding (A + D)

(HNCONH) (HNCONH) Dipole–dipole
Hydrophobic (R) Absorption (R) Ion–dipole (as the dipole)
D Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A)

Hydrophobic (R) Absorption (R) Dipole–dipole
E Pyridine Hydrophilic (N) Basic Solubility (N) Pyridine N atom:

(Azine) Hydrophobic (R) (pKa 1–5) Absorption (R) H-bonding (A)
Dipole–dipole
R:
van der Waals
Hydrophobic
π-π Stacking
Cation-π interactions
Charge transfer interactions
F Amide Hydrophilic Neutral Solubility (CONH) H-bonding (A+ D)
(CONH) Absorption (R) Dipole–dipole
Hydrophobic (R) Ion–dipole (as the dipole)
2. Functional group interactions provided below.
Interacts with Cysteine919 Interacts with Aspartic Interacts with

via a Hydrogen Bonding Acid1046 via a Hydrogen Phenylalanine1047 via a
Interaction. Bonding Interaction. Hydrophobic Interaction.
Functional Group Yes or No Yes or No Yes or No
A No No Yes
B Yes Yes No
C Yes Yes No
D Yes Yes No
E Yes Yes Yes
F Yes Yes No
3. Part A: Possible types of binding interactions are listed below.
Leu285/Val289 Asp391/Glu286 Thr315 Met318 Leu298/Val299/Phe359

Hydrophobic Ionic H-bonding Hydrophobic Hydrophobic
Ion–dipole (as the ion) Dipole–dipole Dipole–dipole van der Waals
Ion–dipole (as the H-bonding (A) π-π Stacking
dipole) Cation-π interactions

Part B: Possible types of binding interactions between amino acids and functional
groups are provided below.
Leu285/Val289 Asp391/Glu286 Thr315 Met318 Leu298/Val299/Phe359
A Hydrophobic Ion–dipole (functional H-bonding (A) Hydrophobic Hydrophobic

group as the dipole) Dipole–dipole π-π Stacking
B Hydrophobic None H-bonding (A) Hydrophobic Hydrophobic

van der Waals Dipole–dipole van der Waals
π-π Stacking
C None Ion–dipole (functional H-bonding (A+D) H-bonding (Met None

group as the dipole) Dipole–dipole is acceptor)
D* None Ion–dipole (functional H-bonding (A+D) H-bonding (Met None

group as the dipole) Dipole–dipole is acceptor)
E** Hydrophobic Ion–dipole (functional H-bonding (A) None Hydrophobic

group as the dipole) Dipole–dipole π-π Stacking
Aniline-like nitrogen atom will not be ionized at physiological pH.

*
Sorafenib
**
Pyridine (azine) nitrogen atom will not be ionized at physiological pH.
Part C: Interaction between the pyridyl nitrogen atom and methionine is shown below.
Part C: Interaction between the pyridyl nitrogen atom and methionine is shown
below.
H-Bond
Acceptor
Nilotinib
H-Bond
Donor
Methionine
Zanamivir and Oseltamivir

1. Acidic and basic function groups are identified along with ranges and ionization state at
pH = 7.2.

4. The halogenated aromatic hydrocarbon, aromatic hydrocarbon, and the pyridine

ring carbon atoms all contribute significantly to the hydrophobic character of
sorafenib. It is important to note that the basic pyridine ring is unlikely to be
ionized at physiological pH (pKa = 6 < pH = 7.4). Although there appears to
be significant hydrophilic character (halogenated aliphatic alkane, urea, ether,
the nitrogen atom of the pyridine, amide) present in this molecule, sorafenib is
practically insoluble in water. The lack of water solubility and clearly identifiable
hydrophobic character allows for passive diffusion of the drug across the cellular
lipid bilayer membrane.
5. Based on the information found in the structure evaluation grid for sorafenib, there
are several functional groups that contribute to the overall hydrophobic character
of the molecule (e.g., halogenated aromatic hydrocarbon, aromatic hydrocarbon,
carbon atoms of pyridine/azine ring). Similar evaluation of nilotinib yields two
aromatic rings, a pyrimidine ring (between functional groups D and E), a pyridine
ring (functional group E), and even some hydrophobic character in the histidine
ring (functional group A) that contribute to the overall hydrophobic character of
the molecule. When you compare the sheer number of functional groups that
contribute to the overall hydrophobic character for each drug, nilotinib wins!
6. The value of lipid-soluble organic salts is to decrease the water solubility and
increase the lipid solubility of the parent drug (in this case sorafenib) (see
Chapter 5). Typically lipid-soluble salts are used in the formation of lipid-soluble
suspensions. In addition, they can improve the oral bioavailability of acid labile
drug molecules and improve the palatability of liquid solutions. p-Toluenesulfonic
acid (tosylic acid) is considered a strong organic acid and forms a strong counter-
ion when dissociated from the drug molecule. Sorafenib is administered as a film-
coated tablet for adults and as a liquid suspension for children.
The value associated with the formation of inorganic salts is due to the improved
aqueous solubility, solvation, and dissolution that results. In general, inorganic
salts enhance the absorption of drugs that are administered orally because they
improve both solvation and dissolution properties.
7. Sorafenib:
N-oxidation
Oxidative N-dealkylation (amide)
Nilotinib:
Benzylic oxidation
N-oxidation

Nilotinib
H-Bond
8. No, when a drug molecule is bound to a serum protein, including serum albumin,
Donor
it cannot undergo metabolic transformations, be eliminated from the body,
or effectively interact with its biological target. Only the fraction of the drug
“unbound” is eligible to exert its therapeutic effect and is subject to metabolic
transformations. It should be noted that extensive proteinMethionine
binding can effectively
increase the half-life of the drug.

1. Acidic and basic function groups are identified along with ranges and ionization state at
pH = 7.2.
1. Acidic and basic function groups are identified along with ranges and ionization
state at pH = 7.2.
Carboxylic acid (Acidic functional group)

Normal pKa range = 2.5 to 5
Guanidine (Basic functional group)

2. The amide and hydroxyl groups can act as hydrogen bond donors and acceptors
and thus can form hydrogen bonds with water. The ether oxygen most likely
2. The amide andthe
contributes hydroxyl
least togroups can act ashowever,
water solubility; hydrogen bond
it can donorsasand
function acceptors and thus
a hydrogen
bond acceptor.
Primary hydroxyl group

(or primary alcohol) Secondary hydroxyl group
(or secondary alcohol)
Secondary hydroxyl group
(or secondary alcohol) Ether oxygen
Amide
3. Zanamivir is a stable mimic of N-acetylsialic acid. As shown below, the structure of
Structurally identical
to N-acetylsialic acid
(with exception
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the double bond)
Primary hydroxyl group APPENDIX: ANSWERS TO CHAPTER QUESTIONS 587
(or primary alcohol) Secondary hydroxyl group
(or secondary alcohol)
Secondary
3. hydroxyl group
The structure of zanamivir contains multiple hydrophilic functional groups that
(or secondary
will alcohol) Ether oxygen
allow it to easily dissolve within the aqueous contents of the GI tract. The
carboxylic acid and the guanidine functional groups will be extensively ionized
at an intestinal pH = 5 which further increases the overall water solubility of the
molecule. Although the structure of zanamivir contains a hydrocarbon chain and
ring, the overall balance between water and lipid solubility hinders its ability to
effectively cross the GI membrane. The oral absorption of zanamivir has been
reported to be between 1% and 5%. Due to this, zanamivir must be administered
via oral inhalation.
Amide
4. Zanamivir is a stable mimic of N-acetylsialic acid. As shown below, the structure of

. Zanamivir is zanamivir
a stable mimic of N-acetylsialic acid. As shown below, the structure of
retains many of the structural features of N-acetylsialic acid, but lacks a
cleavable glycosidic bond.
Structurally identical
to N-acetylsialic acid
(with exception of
the double bond)
Lacks glycosidic bond
Zanamivir
The structural similarity allows zanamivir to interact with neuraminidase in the

. When samethese
comparing manner N-acetylsialic
twoasstructures, acid.
there areIonic
threeorkey
ion-dipole interactions
structural withIn
differences. the
all three
carboxylic acid remain the same, as does the ability to form hydrogen bonds with
the hydroxyl groups and the amide. Because zanamivir lacks a cleavable glycosidic
bond, it can occupy the binding site without being metabolically transformed.
The most significant difference between zanamivir and N-acetylsialic acid is
A the substitution of a secondary hydroxyl group with a guanidine group. Studies
have shown that this basic functional group can A form ionic interactions with
neuraminidase. In summary, zanamivir structurally mimics the natural substrate
for neuraminidase and is ableCto bind to the active site of the enzyme. This
binding inhibits the ability of neuraminidase to cleave N-acetylsialic acid from viral
C
glycoproteins, thus inhibiting the spread of a viral infection.
B Oseltamivir
Zanamivir B

Lacks glycosidic bond
Zanamivir
5. When comparing these two structures, there are three key structural differences.
4. When comparing theseinstances,
In all three two structures, there aregroup
the functional three on
keyoseltamivir
structural is
differences.
less water In all three
soluble (or
more lipid soluble) than the analogous functional group on zanamivir.
A
A
C
C
B Oseltamivir
Zanamivir B
The glycerol side chain of zanamivir (A) is much more water soluble than the alkyl
ether of oseltamivir (A). Although both drug molecules contain a basic functional
group within their structure, the guanidine group in zanamivir (B) is more basic
and will be more highly ionized than the primary amine (B) in oseltamivir. Finally,
the ionizable carboxylic acid of zanamivir (C) has been esterified in oseltamivir
(C). This ethyl ester is no longer acidic, cannot ionize, and therefore generates
a more hydrophobic prodrug. Returning to Question #3, the key reason that
zanamivir is not orally active is that it does not possess adequate lipid solubility
to traverse the GI mucosal membrane. By incorporating these three structural
changes, oseltamivir has a better water/lipid solubility balance that allows it to be
administered orally in the treatment of influenza infections.
6. To solve this problem, we need to use the Henderson-Hasselbalch equation.

5. To solve this problem,
Because we need to
the functional use thea Henderson-Hasselbalch
group, equation.
primary amine, is basic, Because
the ionized the (R-NH +)
form 3
is the Acid Form and the unionized form (R-NH2) is the Base Form.
ሾ ሿ
ൌ ୟ ൅
ሾ ሿ
ሾ ሿ
͸Ǥͷ ൌ ͹Ǥ͹ ൅
ሾ ሿ
ሾ ሿ
െͳǤʹ ൌ
ሾ ሿ

ͲǤͲ͸͵ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This ratio indicates that for every one molecule that contains the functional group in the acid
ͲǤͲ͸͵ ൅ ͳǤͲ ൌ ͳǤͲ͸͵

ൌ ൌ
ͲǤͲ͸͵ ൌ ൌ
ሾ ሿ ͳ ሾ ሿ
This ratio indicates
to correctly that forthe
calculate every one molecule
percentage of thethat containsthat
molecules theare
functional group
ionized and thein the acid
0.063 molecule in Base Form൅+ ͳǤͲ

ͲǤͲ͸͵ 1.0 molecule in Acid Form = 1.063 total molecules
ൌ ͳǤͲ͸͵
ൌ ൌ
ͳ
ൌ ൈ ͳͲͲΨ ൌ ͻͶǤͳΨ
ͳǤͲ͸͵
ͲǤͲ͸͵
ͳǤͲ͸͵
Because the question asks for the percent that will be ionized, the correct answer is
Because the question asks for the percent that will be ionized, the correct answer
is94.1%.
94.1%.
7. This stereoisomer has the opposite stereochemical configuration at all five chiral
centers and has the exact same conformation as zanamivir; therefore, this is the
enantiomer of zanamivir. None of the other stereochemical designations are
correct.
Given that zanamivir as well as oseltamivir exert their antiviral activity by mimicking
N-acetylsialic acid, alteration of the stereochemistry decreases the resemblance to
N-acetylsialic acid and would be predicted to cause a decrease in binding affinity
to neuraminidase and a decreased antiviral effect.
8. Pathway A: Hydrolysis: Phase I transformation. YES, both the ester and amide
8. Pathway A: Hydrolysis:
functional Phase
groups can I transformation.
undergo YES,
hydrolysis. bothhydrolysis
Ester the ester and amide functional
produces the active
metabolite of oseltamivir.
O O O
O O O O O O
N H 2N H 2N
H3C H
OH O OH
O H 2N H 2N C H3 H 2N
Ester hydrolysis Amide hydrolysis Ester and amide

hydrolysis
Pathway B: Allylic oxidation: Phase I transformation. NO, it is not possible

because
Pathway bothoxidation:
B: Allylic allylic carbon
Phaseatoms are alreadyNO,
I transformation. attached
it is nottopossible
heteroatoms.
because both
Additionally, one allylic carbon atom lacks a hydrogen atom that is required for
oxidation.
Already attached
to a heteroatom
Lacks a hydrogen atom

Pathway B: Allylic
Pathway
590B:
oxidation:
Allylic
BASICoxidation:
Phase
CONCEPTSPhase
I transformation.
I transformation.
IN MEDICINAL CHEMISTRY
NO, it is not possible because both
NO, it is not possible because both
Alreadyattached
Already attached
to a heteroatom
to a heteroatom
Lacks a hydrogen
Lacks atom
a hydrogen atom
Already attached
Already attached
to a heteroatom Oseltamivir
to a heteroatom Oseltamivir
C:Pathway
Pathway C: Glucuronide
Glucuronide conjugation:
conjugation: Phase II transformation. YES, it canYES,
Phase II transformation. occuritdirectly
can occur
directly with the
Pathway C: Glucuronide secondary amine
conjugation: PhaseorIIwith the carboxylicYES,
transformation. acid that results
it can occurfrom
directly
Phase I ester hydrolysis.
Pathway D: Z-Oxidation: Phase I, YES

Pathway D: ω-Oxidation: Phase I, YES
Pathway E: Oxidative O-dealkylation: Phase I, YES

Pathway E: Oxidative O-dealkylation: Phase I, YES ANSWERS TO CHAPTER QUESTIONS
APPENDIX: 591
Pathway E: Oxidative O-dealkylation: Phase I, YES
9. Zanamivir is very highly water soluble. Its chemical structure contains two ionizable
functional groups as well as several others that can form hydrogen bonds with
water. As such, zanamivir can be readily excreted without further metabolic
transformation. Remember that the major purpose of drug metabolism is to
enhance the removal of the drug from the body. If a drug molecule can be readily
removed from the body, there is no need for metabolic transformations.


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APP

Functional Group Name Contribution to Water and/or Lipid Solubility

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3. Answers provided in table below.

Electron Donating or Withdrawing Resonance or Induction

Checkpoint Drug 2: Elamipretide

1. Answers provided in the grid below.

E Phenol Hydrophobic (R) Absorption (R)

Part B: As building blocks of endogenous proteins or peptidomimetic drugs, the

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Part D: The second amino acid is a derivative of tyrosine.

3. Answers provided in the grid below.

Amino Acid Side Chain Amino Acid Side

Box Functional Group Name

2. Answers provided in the grid below.

Box Functional Group Name

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Part C: The amidine is not protonated at physiological pH because the

4. Part A: Answers provided in the grid below.

Ether Hydrophilic (O) Water solubility (O) Hydrogen bond acceptor

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7. Functional group and explanation provided below.

9. Part A: The portion of the

Aromatic amine (Basic) Aromatic amine (Basic)

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5. The ionized form of the tertiary amine is shown below.

Checkpoint Drug 2: Elamipretide

1. Answers provided in the grid below.

Character: pKa Value or Range

D Phenol Acidic 9–10

2. Functional group C is an amide. The carbonyl carbon is electron poor due to

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3. The ionization states and acid/base character are provided below.

Stomach (pH=1) Acid/Base Intestine (pH=8) Acid/Base Urine (pH=5) Acid/Base

Functional group A (guanidine) is basic in character with a pKa = ~12.5. It will be

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1. Acidic and basic functional groups are identified below.

Drug Name Acidic Functional Groups Basic Functional Groups

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Efegatran Sulfamethazine Nelfinavir Losartan Isalmadol

Efegatran Sulfamethazine Nelfinavir Losartan Isalmadol

6. Answers provided in the grid below.

7. Part A: Colesevelam contains a neutral quaternary ammonium salt as a component

Part C: Repaglinide (carboxylic acid), gliclazide (sulfonylurea), ciprofloxacin

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8. Part A: Ionizable functional groups are listed in the table below.

Acidic Functional Groups Basic Functional Groups

Acidic Character, Basic Character, or Both Acidic and Basic Character

Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

9. The acidic, (DFKRIWKHGUXJPROHFXOHVEHORZFRQWDLQVDWOHDVWRQHLRQL]DEOHIXQFWLRQDOJUR

Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

4. Part A: As determined in question 1B, the pK of 4.3 belongs to the acidic

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9. The acidic, (DFKRIWKHGUXJPROHFXOHVEHORZFRQWDLQVDWOHDVWRQHLRQL]DEOHIXQFWLRQDOJUR

ሾ ሿ ͲǤͲ͸͵ ሾ ሿ

ൌ ൌ

ͲǤͲ͸͵

ሾ ሿ Unauthenticated | Downloaded 07/13/21 09:53 AM UTC

ሾ ሿ ͲǤʹͲ ሾ ሿ

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ൌ ͵Ǥͷ ൅ ʹǤ͵

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ሾ ሿ ͲǤͲͲͲͳ ሾ ሿ

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ͳǤͲ

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ሾ ሿ ͲǤͲͳ ሾ ሿ

ͲǤͲͳ ൅ ͳǤͲ ൌ ͳǤͲͳ

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ͳǤͲ

ͲǤͲͳ ൅ ͳǤͲ ൌ ͳǤͲͳ

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